Sustained release matrix systems for highly soluble drugs

ABSTRACT

Disclosed are sustained release oral solid dosage forms comprising a therapeutically effective amount of a medicament having a solubility of more than about 10 g/l; a pH modifying agent; and a sustained release matrix comprising a gelling agent, said gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, said dosage form providing a sustained release of said medicament after oral administration to human patients.

[0001] This application claims the benefit of provisional applicationSerial No. 60/157,200 filed Sep. 30, 1999, the disclosure of which ishereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The advantages of controlled release products are well known inthe pharmaceutical field and include the ability to maintain a desiredblood level of a medicament over a comparatively longer period of timewhile increasing patient compliance by reducing the number ofadministrations necessary to achieve the same. These advantages havebeen attained by a wide variety of methods. For example, differenthydrogels have been described for use in controlled release medicines,some of which are synthetic, but most of which are semi-synthetic or ofnatural origin. A few contain both synthetic and non-synthetic material.However, some of the systems require special process and productionequipment, and in addition some of these systems are susceptible tovariable drug release.

[0003] Oral controlled release delivery systems should ideally beadaptable so that release rates and profiles can be matched tophysiological and chronotherapeutic requirements.

[0004] For the most part, the release rate of oral delivery systems havebeen classified according to the mechanism of release, such as zeroorder, first order, second order, pseudo-first order, and the like,although many pharmaceutical compounds release medicament via other,complicated mechanisms.

[0005] First order mechanisms refer to situations where the reactionrate is dependent on the concentration of the reacting substance (andtherefore is dependent on the first power of the reactant). In suchmechanisms, the substance decomposes directly into one or more products.

[0006] Second order mechanisms occur when the experimentally determinedrate of reaction is proportional to the concentration of each of tworeactants, or to the second power of the concentration of one reactant.

[0007] Pseudo first order reactions are generally defined as secondorder reactions which behave as though they are governed by a firstorder mechanism, and occur, for example, when the amount of one reactingmaterial is manipulated by being present in great excess or beingmaintained at a constant concentration as compared to the othersubstance. In such circumstances, the reaction rate is determined by themanipulated substance.

[0008] Zero order mechanisms refer to situations where the reaction rateis independent of the concentration of the reacting substance (andtherefore is dependent on the zero power of the reactant), the limitingfactor being something other than the concentration of the reactingsubstance (e.g., the medicament). The limiting factor in a zero ordermechanism may be, for example, the solubility of the reacting substanceor the light intensity in photochemical reactions.

[0009] As previously mentioned, however, many chemical reactions are notsimple reactions of zero-, first-, or second-order, and the like, andinstead comprise a combination of two or more reactions.

[0010] Moreover, other factors may influence the reaction rate,including temperature, pH, food effect variability, ions and ionicstrength dependency, viscosity dependency, corrosion/erosionvariability, content uniformity problems, flow and weight uniformityproblems, carrying capacity and mechanical strength problems,hydrolysis, photochemical decomposition, interaction between components(such as interactions between the drug and other ingredients in theformulation, such as buffers, preservatives, and the like), theconcentration of solvents of low dielectric constant (when the reactioninvolves oppositely charged ions), etc.

[0011] While many controlled and sustained release formulations arealready known, certain soluble to highly soluble drugs presentformulation difficulties when included in such formulations. Sustainedrelease formulations with soluble drugs are susceptible to “dosedumping”. This occurrence is where the release of the active ingredientis delayed, but when release is initiated, the rate is extremely high.This elevated release rate is associated with blood plasma fluctuationswhich can possibly result in decreased therapeutic effect or increasedtoxicity. These are the same problems which sustained releaseformulations are supposed to solve.

[0012] Further, it is often not possible to readily predict whether aparticular sustained release formulation will provide the desiredsustained release for a soluble to highly soluble drug. It has generallybeen found that it is necessary to carry out considerableexperimentation to obtain sustained release formulations providing thedesired bioavailability of such drugs when ingested.

[0013] In order to compensate for the unpredictability associated withhaving a controlled release formulation provide the desired sustainedrelease for a soluble to highly soluble drug, it is sometimes considereddesirable to provide a formulation with bi-modal or multi-phasickinetics. Bimodal or multi-phasic release maybe characterized by aninitial high rate followed by a slower rate as the dosage form passesthe upper portion of the small intestine where absorption is maximum andfinally another higher rate as the dosage form passes into the furtherend of the intestine where absorption is less than before.

[0014] Bimodal release is considered to be advantageous for a number ofreasons, including but not limited to the fact that bimodal releaseallows the formulator to compensate for changing absorption rates of themedicament in the gastrointestinal tract by providing a rapid onset ofaction (when the formulation is located in the stomach) and compensatefor relatively slow absorption by providing a relatively rapid releaserate (e.g., when the formulation is located in the large intestine).

[0015] Bimodal release formulations have been provided in a number ofdifferent manners to date.

[0016] For example, International Publication Number WO/87/00044describes therapeutic formulations which are said to have bimodalrelease characteristics. WO 87/00044 describes a carrier base materialfor therapeutically active medicaments in a solid dosage formulationthat are said to produce a bimodal controlled release profilecharacterized by a rapid initial release of medicament followed by asubstantially constant rate of release for a period of time, after whichthe release rate is greater than the constant rate previously observed.The carrier based material comprises bimodalhydroxypropylmethylcellulose ethers with a methoxy content of 19-30%, ahydroxy propoxy content of 4-12%, a viscosity of 40-19,000 cps, anaverage molecular weight of 20,000-140,000, and which demonstrates abimodal release profile in accordance with an assay method describedtherein. The bimodal hydroxypropylmethylcelluloses comprise 5-99% byweight of the total formulation, depending upon the active ingredientand length of drug released desire.

[0017] A. C. Shah et al., “Gel-Matrix Systems Exhibiting BimodalControlled Release For Oral Drug Delivery”, Journal of ControlledRelease, 9(1989), pp. 169-175, further reported that certain “types” ofhydroxypropylmethylcellulose ethers are found to display a bimodal drugrelease profile. However, in that study, series ofhydroxypropylmethylcellulose ether polymers were found to providebimodal and non-bimodal release profiles from polymer-drug matrixtablets, which results appeared to depend upon the supplier of thepolymer (and therefore upon, e.g., the method of manufacture, ioniccomposition, variations in the distribution of substituent groups, ordistribution of molecular weight fractions).

[0018] P. Giunchedi et al., “Ketoprofen Pulsatile Absorption From‘Multiple Unit’ Hydrophilic Matrices” International Journal ofPharmaceutics, 77(1991), pp 177-181 described an extended release oralformulation of Ketoprofen comprising a multiple unit formulationconstituted by four hydrophilic matrices of identical composition, eachcontaining 50 mg of drug and prepared with hydroxypropylmethylcellulose(Methocel.RTM.) and placed in a gelatin capsule. Pulsatile plasma levels(2 peaks at 2nd and 8th hours after dosing) were said to be obtained,whereas in vitro tests resulted in a fairly constant drug release.

[0019] U. Conte et al., “A New Ibuprofen Pulsed Release Oral DosageForm”, Drug. Development And Industrial Pharmacy, 15(14-16), pp2583-2596 (1989) reported that a pulsed released pattern was obtainedfrom a 3-layer tablet wherein two layers contained a dose of drug, andan intermediate layer acted as a control element separating the druglayers. The control element was a mixture of water-swellable polymers(hydroxypropylmethylcelluloses). An outer film of an impermeable polymercoated the tablet. A superdisintegrant (sodium starch glycolate andcross-linked polyvinyl pyrrolidone) was included in the drug layers.

[0020] K. A. Kahn et al, “Pharmaceutical Aspects And In-Vivo PerformanceOf Brufen Retard—An Ibuprofen SR Matrix Tablet”, Proced. Intern. Symp.Control. Rel. Bioact. Mater., 18(1991), Controlled Release Society,Inc., describes a formulation containing 800 mg of ibuprofen which issaid to provide a bimodal release pattern. The release retarding agentutilized therein was xanthan gum. The ingredients were blended to theappropriate xanthan gum content, and thereafter compressed into tabletsand film coated. The amount of xanthan gum included inversely affectedthe rate of drug release. An increase in drug particle size or quantityof film-coat per tablet did not significantly effect the rate of drugrelease. Although an increase in particle size of the xanthan gum causeda more pronounced burst effect, the application of the film-coatovercame this burst effect. The rapid initial release of the medicamentwas hypothesized to be related to changes in the formation of the gellayer, wherein larger particles gel more slowly and are sloughed offbefore a coherent matrix can form.

[0021] In our U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, herebyincorporated by reference, we reported that a controlled releaseexcipient which is comprised of synergistic heterodispersepolysaccharides (e.g., a heteropolysaccharide such as xanthan gum incombination with a polysaccharide gum capable of cross-linking with theheteropolysaccharide, such as locust bean gum) is capable of processinginto oral solid dosage forms using either direct compression, followingaddition of drug and lubricant powder, conventional wet granulation, ora combination of the two. The release of the medicament from theformulations therein proceeded according to zero-order or first-ordermechanisms.

[0022] Our own U.S. Pat. No. 5,472,711 and 5,478,574, herebyincorporated by reference, we report a formulation capable of providingmulti-phasic or bi-phasic controlled release of a therapeutically activemedicament in vitro by incorporating an effective amount of apharmaceutically acceptable surfactant with the above-referencedexcipient.

[0023] An example of a highly soluble drug used in the present inventionis diltiazem, which is a benzothiazine derivative possessing calciumantagonist activity. Diltiazem is widely used in the treatment ofhypertension and angina. Accordingly, a great deal of attention has beengiven to the preparation of sustained release diltiazem which providesan acceptable release profile.

[0024] For example U.S. Pat. Nos. 4,894,240 and 5,364,620 (Geoghegan, etal.) describe a diltiazem pellet formulation suitable for once dailyadministration. This formulation comprises a diltiazem core inassociation with an organic acid, surrounded by an insoluble multi-layermembrane. The membrane allows the release of diltiazem from the pelletat a rate allowing controlled absorption over a 24 hour period followingadministration.

[0025] Other techniques have been described in the prior art forpreparing sustained release diltiazem formulations. For example, U.S.Pat. No. 5,419,917, (Chen et al.) describes a composition which controlsthe rate of release of diltiazem from a hydrogel using apharmaceutically effective ionizable compound.

[0026] Another example of a highly soluble drug used in the presentinvention is oxybutynin. Oxybutynin is widely used in the treatment ofurological disorders, e.g., hyperactive bladder. Our own U.S. Pat. No.5,399,359 discloses an oxybutynin sustained release formulationcomprising a pharmaceutically effective amount of oxybutynin dispersedwithin a sustained release matrix comprising a gelling agent, aneffective amount of a pharmaceutically acceptable water-soluble cationiccross-linking agent which cross-links with the gelling agent when theformulation is exposed to an environmental fluid, e.g., gastrointestinalfluid, and an inert diluent.

OBJECTS AND SUMMARY OF THE INVENTION

[0027] It is an object of the present invention to provide abioavailable sustained release formulation for soluble to highly solubletherapeutically active medicaments.

[0028] It is a further object of the present invention to provide aformulation which can provide multi-phasic or bi-phasic controlledrelease for soluble to highly soluble medicaments.

[0029] It is a further object of the present invention to provide amethod for preparing a bioavailable sustained release formulation forsoluble to highly soluble therapeutically active medicaments.

[0030] It is yet another object of the present invention to provide asustained release matrix which may be used in the preparation of asustained release oral solid dosage form of soluble to highly solubletherapeutically active medicaments.

[0031] It is a further object of the present invention to provide asustained release matrix which is suitable for providing, when combinedwith a medicament, a sustained release formulation which providestherapeutically effective blood levels of the medicament for e.g., 12 or24 hours.

[0032] It is a further object of the invention to provide a diltiazemsustained release matrix formulation which provides a plasma profilesimilar to commercially available sustained release formulations, e.g.,Cardizem CD.

[0033] It is a further object of the invention to provide a oxybutyninsustained release matrix formulation which provides a plasma profilesimilar to commercially available sustained release formulations, e.g.,Ditropan XL.

[0034] The above-mentioned objects and others are achieved by virtue ofthe present invention, which relates in part to the surprising discoverythat the incorporation of a pH modifying agent into a dosage formcomprising a gelling agent, facilitates the release of the drug from thedosage form and provides a high bioavailability.

[0035] In certain embodiments, the sustained release oral solid dosageform comprises a therapeutically effective amount of a medicament havinga solubility of more than about 10 g/l; a pH modifying agent; and asustained release matrix comprising a gelling agent, the gelling agentcomprising a heteropolysaccharide gum and a homopolysaccharide gumcapable of cross-linking the heteropolysaccharide gum when exposed to anenvironmental fluid. Preferably, the dosage form provides a sustainedrelease of the medicament for at least about 12 hours, preferably atleast about 24 hours.

[0036] In certain embodiments, the dosage form further comprises a) apharmaceutically acceptable surfactant which can provide a multi-phasicrelease of the drug; b) an inert diluent selected from, e.g., amonosaccharide, a disaccharide, a polyhydric alcohol, or mixturesthereof; c) a hydrophobic material to slow the hydration of the gellingagent; and/or d) an effective amount of a pharmaceutically acceptableionizable gel strength enhancing agent suitable for modifying therelease rate from the gel which is formed when the controlled releaseformulation is exposed to an environmental fluid. In a preferredembodiment, the formulation of the present invention comprises a tablet.

[0037] In a preferred embodiment of the invention, the ratio ofmedicament to gelling agent is preferably from about 10:1 to about 1:10,more more preferably from about 5:1 to about 1:5, and most preferablyfrom about 1.25:1 to about 2:1.

[0038] The present invention is also related to a method for providing asustained release formulation of a medicament having high solubility inwater, comprising preparing a matrix comprising a gelling agentcomprising a heteropolysaccharide gum and a homopolysaccharide gumcapable of cross-linking said heteropolysaccharide gum when exposed toan environmental fluid; an optional ionizable gel strength enhancingagent, an optionally inert pharmaceutical diluent; and an optionalhydrophobic material, and thereafter adding a soluble to highly solublemedicament, a pH modifying agent and an optional pharmaceuticallyacceptable surfactant. Thereafter the resulting mixture is tableted suchthat a product is obtained having a ratio of medicament to gelling agentfrom about 10:1 to about 1:10, more preferably from about 5:1 to about1:5, and most preferably from about 1.25:1 to about 2:1, such that a gelmatrix is created when the tablet is exposed to an environmental fluidand such that the tablets each contain a therapeutically effectiveamount of the medicament. The resulting tablet provides therapeuticallyeffective blood levels of the medicament for at least about 12 hours,and preferably about 24 hours.

[0039] The present invention is further related to a method of treatinga patient by orally administering an oral solid dosage form as set forthabove.

[0040] In certain preferred embodiments of the invention, the matrix canbe prepared from a pre-granulated sustained release excipientcomprising, e.g. from about 10 to about 99% by weight of a gellingagent, from about 0 to about 20% by weight of an ionizable gel strengthenhancing agent, from about 1 to about 89% by weight of an inertpharmaceutical diluent, and from about 1 to about 20% of a hydrophobicmaterial.

[0041] In other preferred embodiments the mixture of the matrix andinert diluent are granulated before the addition of the medicament, witha dispersion or solution of the hydrophobic material in an amountsufficient to slow the hydration of the matrix without disrupting thesame.

[0042] In other preferred embodiments of the invention, a first portionof the medicament is introduced during the granulation of the excipient,and a second portion of the drug is introduced extragranularly, or afterthe granulation step. Such an embodiment provides an initial rapidrelease of the medicament.

[0043] In preferred embodiments, the medicament is highly soluble, i.e.,has a solubility of more than about 100 g/l.

[0044] In other preferred embodiment, the medicament comprises a calciumchannel blocker, preferably a benzothiazine, most preferably diltiazemor a pharmaceutically acceptable salt thereof.

[0045] In other preferred embodiments, the medicament comprises anantispasmodic, preferably oxybutynin or a pharmaceutically acceptablesalt thereof.

[0046] By “sustained release” it is meant for purposes of the presentinvention that the therapeutically active medicament is released fromthe formulation at a controlled rate such that therapeuticallybeneficial blood levels (but below toxic levels) of the medicament aremaintained over an extended period of time, e.g., at least about 12 houror at least about 24 hours.

[0047] By “bioavailable” it is meant for purposes of the presentinvention that the therapeutically active medicament is absorbed fromthe sustained release formulation and becomes available in the body atthe intended site of drug action, preferably within 80% of a referencestandard (based on comparison of the AUC).

[0048] By “soluble”, it is meant that the therapeutically activemedicament has an aqueous solubility of more than about 10 grams perliter (g/l).

[0049] By “highly soluble”, it is meant that the therapeutically activemedicament has an aqueous solubility of more than about 100 grams perliter (g/l).

[0050] The term “environmental fluid” is meant for purposes of thepresent invention to encompass, e.g., an aqueous solution, orgastrointestinal fluid.

[0051] The term “pH modifying agent” is meant for purposes of thepresent invention to mean any substance which decreases the ionizationof the medicament, whereby the release of the drug from the hydrogelmatrix and into solution is facilitated.

[0052] The term “Cmax” is meant for purposes of the present invention tomean then maximum plasma concentration of a medicament achieved afteradministration of a dosage form in accordance with the invention.

[0053] The term “Tmax” is meant for purposes of the present invention tomean the elapsed time from administration of a dosage form to the timethe Cmax of the medicament is achieved

[0054] The term “W₅₀”¹ is meant for purposes of the present invention tomean the time period measured by the width of the plasma concentrationcurve at 50% of the height of the Cmax.

[0055] For purposes of the present invention, the dosage form can havebi-modal kinetics, and accordingly, there can be multiple Cmaxs, Tmaxsand W₅₀s for the disclosed dosage forms.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The following drawings are illustrative of embodiments of theinvention and are not meant to limit the scope of the invention asencompassed by the claims.

[0057]FIG. 1 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 1 and 2.

[0058]FIG. 2 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 3 and 4.

[0059]FIG. 3 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 5 and 6.

[0060]FIG. 4 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 7 and 8.

[0061]FIG. 5 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 9 and 10.

[0062]FIG. 6 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 11 and 12.

[0063]FIG. 7 is a graphical representation of the % release rate overtime for Examples 11 and 12.

[0064]FIG. 8 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 13 and 18.

[0065]FIG. 9 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 19 and 20.

[0066]FIG. 10 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 21-23.

[0067]FIG. 11 is a graphical representation of the mean plasma diltiazemconcentration (ng/ml) over time for Example 24 and for a referencestandard (Cardizem CD 240 mg).

[0068]FIG. 12 is a graphical representation of the mean plasma diltiazemconcentration (ng/ml) over time for Examples 25 and for a referencestandard (Cardizem CD 240 mg).

[0069]FIG. 13 is a graphical representation of the dissolution (meanpercent dissolved over time) for Examples 26 and 27.

[0070]FIG. 14 is a graphical representation comparing the dissolution(mean percent dissolved over time) of Example 37 and for a referencestandard (Ditropan XL).

DETAILED DESCRIPTION

[0071] The sustained release matrix of the present invention can be aheterodisperse excipient (as previously reported in our U.S. Pat. Nos.4,994,276, 5,128,143, and 5,135,757) which can comprise a gelling agentof both hetero- and homo-polysaccharides which exhibit synergism, e.g.,the combination of two or more polysaccharide gums produce a higherviscosity and faster hydration than that which would be expected byeither of the gums alone, the resultant gel being faster-forming andmore rigid.

[0072] The term “heteropolysaccharide” as used in the present inventionis defined as a water-soluble polysaccharide containing two or morekinds of sugar units, the heteropolysaccharide having a branched orhelical configuration, and having excellent water-wicking properties andimmense thickening properties.

[0073] An especially preferred heteropolysaccharide is xanthan gum,which is a high molecular weight (>10⁶) heteropolysaccharide. Otherpreferred heteropolysaccharides include derivatives of xanthan gum, suchas deacylated xanthan gum, the carboxymethyl ether, and the propyleneglycol ester.

[0074] The homopolysaccharide gums used in the present invention whichare capable of cross-linking with the heteropolysaccharide include thegalactomannans, i.e., polysaccharides which are composed solely ofmannose and galactose. Galactomannans which have higher proportions ofunsubstituted mannose regions have been found to achieve moreinteraction with the heteropolysaccharide. Locust bean gum, which has ahigher ratio of mannose to the galactose, is especially preferred ascompared to other galactomannans such as guar and hydroxypropyl guar.

[0075] The controlled release properties of the controlled releaseformulations of the present invention maybe optimized when the ratio ofheteropolysaccharide gum to homopolysaccharide material is about 1:1.5,although heteropolysaccharide gum in an amount of from about 10 to about90 percent or more by weight of the heterodisperse polysaccharidematerial provides an acceptable slow release product. The combination ofany homopolysaccharide gums known to produce a synergistic effect whenexposed to aqueous solutions may be used in accordance with the presentinvention. It is also possible that the type of synergism which ispresent with regard to the gum combination of the present inventioncould also occur between two homogeneous or two heteropolysaccharides.Other acceptable gelling agents which may be used in the presentinvention include those gelling agents well-known in the art. Examplesinclude vegetable gums such as alginates, carrageenan, pectin, guar gum,modified starch, hydroxypropylmethylcellulose, methylcellulose, andother cellulosic materials such as sodium carboxymethylcellulose andhydroxypropyl cellulose. This list is not meant to be exclusive.

[0076] The inert diluent of the sustained release excipient preferablycomprises a pharmaceutically acceptable saccharide, including amonosaccharide, a disaccharide, or a polyhydric alcohol, and/or mixturesof any of the foregoing. Examples of suitable inert pharmaceuticalfillers include sucrose, dextrose, lactose, microcrystalline cellulose,fructose, xylitol, sorbitol, starches, mixtures thereof and the like.However, it is preferred that a soluble pharmaceutical filler such aslactose, dextrose, sucrose, or mixtures thereof be used. The inertdiluent or filler may alternatively comprise a pre-manufactured directcompression diluent as set forth below.

[0077] For example, it is possible to dry mix the ingredients of thesustained release excipient without utilizing a wet granulation step.This procedure may be utilized, for example, where a wet granulation isto be accomplished when the active ingredient is directly added to theingredients of the sustained release excipient. On the other hand, thisprocedure may also be used where no wet granulation step whatsoever iscontemplated. If the mixture is to be manufactured without a wetgranulation step, and the final mixture is to be tableted, it ispreferred that all or part of the inert diluent comprise apre-manufactured direct compression diluent. Such direct compressiondiluents are widely used in the pharmaceutical arts, and may be obtainedfrom a wide variety of commercial sources. Examples of suchpre-manufactured direct compression excipients include Emcocel®(microcrystalline cellulose, N.F.), Emdex® (dextrates, N.F.), andTab-Fine® (a number of direct-compression sugars including sucrose,fructose and dextrose), all of which are commercially available fromPenwest Pharmaceuticals Co., Patterson, New York). Other directcompression diluents include Anhydrous lactose (Lactose N.F., anhydrousdirect tableting) from Sheffield Chemical, Union, N.J. 07083; Elcems®G-250 (powdered cellulose), N.F.) from Degussa, D-600 Frankfurt (Main)Germany; Fast-Flo Lactose® (Lactose, N.F., spray dried) from ForemostWhey Products, Banaboo, Wis. 53913; Maltrin® (Agglomerated maltodextrin)from Grain Processing Corp., Muscatine, Iowa 52761; Neosorb 60®(Sorbitol, N.F., direct-compression from Roquet Corp., 645 5th Ave., NewYork, N.Y. 10022; Nu-Tab® (Compressible sugar, N.F.) from IngredientTechnology, Inc., Pennsauken, N.J. 08110; Polyplasdone XL®(Crospovidone, N.F., cross-linked polyvinylpyrrolidone) from GAF Corp.,New York, N.Y. 10020; Primojel® (Sodium starch glycolate, N.F.,carboxymethyl starch) from Generichem Corp., Little Falls, N.J. 07424;Solka Floc® (Cellulose floc) from Penwest Pharmaceuticals Co.,Patterson, N.Y. 10512; Spray-dried lactose® (Lactose N.F., spray dried)from Foremost Whey Products, Baraboo, Wis. 53913 and DMV Corp., Vehgel,Holland; and Sta-Rx 1500® (Starch 1500) (Pregelatinized starch, N.F.,compressible) from Colorcon, Inc., West Point, Pa. 19486.

[0078] In general, the formulation may be prepared as a directlycompressible diluent, for example, by wet granulating, spray dryinglactose or as a premixed direct compression diluent by art knownmethods. For purposes of the present invention, these specially treatedinert diluents will be referred to as “directly compressible” inertdiluents.

[0079] In certain embodiments, the ingredients of the sustained releaseexcipient can be pre-manufactured. However, in other embodiments theactive drug can be added to the excipient ingredients and that mixturemelt granulated to form a granulation. Finally, where a surfactant isused, the surfactant comprising the solubilized or dispersed diltiazemor oxybutynin can be added directly to the mixture of ingredients.

[0080] In further embodiments of the present invention, the directlycompressible inert diluent which is used in conjunction with thesustained release pharmaceutical excipient of the present invention isan augmented microcrystalline cellulose as disclosed in U.S. patentapplication Ser. No. 08/370,576, filed Jan. 9, 1995, and entitled“PHARMACEUTICAL EXCIPIENT HAVING IMPROVED COMPRESSIBILITY”, by J.Staniforth, B. Sherwood and E. Hunter, hereby incorporated by referencein its entirety. The augmented microcrystalline cellulose describedtherein is commercially available under the tradename “Prosolv” fromPenwest Pharmaceuticals Co.

[0081] An effective amount of a pharmaceutically acceptable surfactantcan also be added to the above-mentioned ingredients of the excipient,or added at the time the medicament is added, in order to increase thebioavailability of the medicament. An example of a suitable surfactantis docusate sodium in an amount up to about 15% by weight of the soliddosage form. An especially preferred surfactant is sodium lauryl sulfatein an amount up to about 15% by weight of the solid dosage form.

[0082] In one embodiment, the surfactant is dissolved in a suitablesolvent such as water, and is thereafter added to the blended mixture ofthe sustained release excipient and the medicament. This allows thesurfactant to wet the particles of the excipient such that when thesolvent evaporates the particles of the medicament which precipitate aretiny and do not aggregate. A granulate of the medicament and thesurfactant is obtained which is preferably finely and homogeneouslydispersed in the excipient.

[0083] In certain embodiments of the present invention, e.g. wherein themedicament is diltiazem or oxybutynin, the surfactant is included in anamount e.g., from about 0.1% to about 5%, or from about 1% to about 15%of the final product, by weight. However, the upper limit of surfactantincluded can be higher than 15%. One limiting factor is that the finalproduct should provide a pharmaceutically acceptable formulation. Forexample, in the case of tablets, the upper limit of the amount ofsurfactant included is determined by the production of apharmaceutically acceptable tablet, e.g., a tablet which has afriability of less than about 1% and a hardness of 6-8 kg.

[0084] The surfactants which may be used in the present inventiongenerally include pharmaceutically acceptable anionic surfactants,cationic surfactants, amphoteric (amphipathic/amphophilic) surfactants,and non-ionic surfactants. Suitable pharmaceutically acceptable anionicsurfactants include, for example, monovalent alkyl carboxylates, acyllactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalentalkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates,sulfuric acid esters, alkyl sulfates (including sodium lauryl sulfate(SLS)), ethoxylated alkyl sulfates, ester linked sulfonates (includingdocusate sodium or dioctyl sodium succinate (DSS)), alpha olefinsulfonates, and phosphated ethoxylated alcohols.

[0085] Suitable pharmaceutically acceptable cationic surfactantsinclude, for example, monoalkyl quaternary ammonium salts, dialkylquaternary ammonium compounds, amidoamines, and aminimides.

[0086] Suitable pharmaceutically acceptable amphoteric(amphipathic/amphophilic) surfactants, include, for example,N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, and N-alkyl6-aminoproprionates.

[0087] Other suitable surfactants for use in conjunction with thepresent invention include polyethyleneglycols as esters or ethers.Examples include polyethoxylated castor oil, polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil. Commercially available surfactants whichcan be used are known under trade names Cremophor, Myrj, Polyoxyl 40stearate, Emerest 2675, Lipal 395 and PEG 3350.

[0088] The pH modifying agent facilitates the release of the drug fromthe matrix and is present from about 1% to about 50%; from about 1% toabout 25% from about 1% to about 15%; or from about 1% to about 10% byweight of the final dosage form. In preferred embodiments, the pHmodifying agent is an organic acid such as citric acid, succinic acid,fumaric acid, malic acid, maleic acid, glutaric acid or lactic acid.

[0089] The ionizable gel strength enhancing agent which is optionallyused in conjunction with the present invention may be monovalent ormultivalent metal cations. The preferred salts are the inorganic salts,including various alkali metal and/or alkaline earth metal sulfates,chlorides, borates, bromides, citrates, acetates, lactates, etc.Specific examples of suitable ionizable gel strength enhancing agentinclude calcium sulfate, sodium chloride, potassium sulfate, sodiumcarbonate, lithium chloride, tripotassium phosphate, sodium borate,potassium bromide, potassium fluoride, sodium bicarbonate, calciumchloride, magnesium chloride, sodium citrate, sodium acetate, calciumlactate, magnesium sulfate and sodium fluoride. Multivalent metalcations may also be utilized. However, the preferred ionizable gelstrength enhancing agent are bivalent. Particularly preferred salts arecalcium sulfate and sodium chloride. The ionizable gel strengthenhancing agent of the present invention are added in an amounteffective to obtain a desirable increased gel strength due to thecross-linking of the gelling agent (e.g., the heteropolysaccharide andhomopolysaccharide gums). In alternate embodiments, the ionizable gelstrength enhancing agent is included in the sustained release excipientof the present invention in an amount from about 1 to about 20% byweight of the sustained release excipient, and in an amount 0.5% toabout 16% by weight of the final dosage form.

[0090] In certain embodiments of the present invention, the sustainedrelease matrix of the present invention comprises a sustained releaseexcipient which comprises from about 10 to about 99 percent by weight ofa gelling agent comprising a heteropolysaccharide gum and ahomopolysaccharide gum, from about 0 to about 20 percent by weight of anionizable gel strength enhancing agent, and from about 1 to about 89percent by weight of an inert pharmaceutical diluent. In otherembodiments, the sustained release excipient comprises from about 10 toabout 75 percent gelling agent, from about 2 to about 15 percentionizable gel strength enhancing agent, and from about 30 to about 75percent inert diluent. In yet other embodiments, the sustained releaseexcipient comprises from about 30 to about 75 percent gelling agent,from about 5 to about 10 percent ionizable gel strength enhancing agent,and from about 15 to about 65 percent inert diluent.

[0091] The sustained release excipient of the present invention (with orwithout the optional ionizable gel strength enhancing agent) may befurther modified by incorporation of a hydrophobic material which slowsthe hydration of the gums without disrupting the hydrophilic matrix.This is accomplished in alternate embodiments of the present inventionby granulating the sustained release excipient with the solution ordispersion of a hydrophobic material prior to the incorporation of themedicament. The hydrophobic polymer may be selected from analkylcellulose such as ethylcellulose, other hydrophobic cellulosicmaterials, polymers or copolymers derived from acrylic or methacrylicacid esters, copolymers of acrylic and methacrylic acid esters, zein,waxes, shellac, hydrogenated vegetable oils, and any otherpharmaceutically acceptable hydrophobic material known to those skilledin the art. The amount of hydrophobic material incorporated into thesustained release excipient is that which is effective to slow thehydration of the gums without disrupting the hydrophilic matrix formedupon exposure to an environmental fluid. In certain preferredembodiments of the present invention, the hydrophobic material isincluded in the sustained release excipient in an amount from about 1 toabout 20 percent by weight. The solvent for the hydrophobic material maybe an aqueous or organic solvent, or mixtures thereof.

[0092] In embodiments where the sustained release excipient of thepresent invention has been pre-manufactured, it is then possible toblend the same with the medicament, e.g., in a high shear mixer. Incertain especially preferred embodiments, the medicament is atherapeutically effective benzothiazine which are useful for thetreatment of circulatory disorders and high blood pressure. Anespecially preferred dihydropyridine is diltiazem. Useful formulationsof diltiazem generally contain daily doses from about 30 to about 500mg, preferably from about 120 mg to about 480 mg. In certain preferredembodiments of the present invention, the dosage form includes a dosageof diltiazem in an amount of 120 mg, 180 mg, 240 mg, or 300 mg for 24hour formulations; and a dosage of diltiazem in an amount of 60 mg, 90mg and 120 mg for 12 hour formulations.

[0093] In certain other especially preferred embodiments, the medicamentis oxybutynin which is useful for the treatment of urological disorders.Useful formulations of oxybutynin generally contain daily doses fromabout 2.5 mg to about 50 mg, e.g., from about 2.5 mg to about 25 mg for12 hour formulations and from about 5 mg to about 50 mg for 24 hourformulations. In certain preferred embodiments of the present invention,the dosage form includes a dosage of oxybutynin in an amount of 5 mg, 10mg, or 15 mg for 24 hour formulations.

[0094] An effective amount of any generally accepted pharmaceuticallubricant, including calcium or magnesium soaps is preferably added tothe mixture of ingredients (including medicament) prior to compressionof the mixture into oral solid dosage forms, such as tablets. An exampleof a suitable lubricant is magnesium stearate in an amount of about 0.5to about 3% by weight of the solid dosage form. An especially preferredlubricant is sodium stearyl fumarate, NF, commercially available underthe trade name Pruve from Penwest Pharmaceuticals Co.

[0095] The sustained release excipients of the present invention haveuniform packing characteristics over a range of different particle sizedistributions and are capable of processing into the final dosage form(e.g., tablets) using either direct compression, following addition ofdrug and lubricant powder, or conventional wet granulation.

[0096] The properties and characteristics of a specific excipient systemprepared according to the present invention is dependent in part on theindividual characteristics of the homo and heteropolysaccharideconstituents, in terms of polymer solubility, glass transitiontemperatures etc., as well as on the synergism both between differenthomo- and heteropolysaccharides and between the homo andheteropolysaccharides and the inert saccharide constituent(s) inmodifying dissolution fluid-excipient interactions.

[0097] The combination of the gelling agent (i.e., a mixture of xanthangum and locust bean gum) with the inert diluent, with or without theionizable gel strength enhancing agent and hydrophobic polymer, providesa ready-to-use sustained release excipient product in which a formulatorneed only blend the desired active medicament, the pH modifying agent,the surfactant and an optional lubricant with the excipient beforecompressing the mixture to form slow release tablets. The excipient maycomprise a physical admix of the gums along with a soluble excipientsuch as compressible sucrose, lactose or dextrose, although it ispreferred to granulate or agglomerate the gums with plain (i.e.,crystalline) sucrose, lactose, dextrose, etc., to form an excipient. Thegranulate form has certain advantages including the fact that it can beoptimized for flow and compressibility; it can be tableted, formulatedin a capsule, extruded and spheronized with an active medicament to formpellets, etc.

[0098] The pharmaceutical excipients prepared in accordance with thepresent invention may be prepared according to any agglomerationtechnique to yield an acceptable excipient product. In wet granulationtechniques, the desired amounts of the heteropolysaccharide gum, thehomopolysaccharide gum, and the inert diluent are mixed together andthereafter a moistening agent such as water, propylene glycol, glycerol,alcohol or the like is added to prepare a moistened mass. Next, themoistened mass is dried. The dried mass is then milled with conventionalequipment into granules. Therefore, the excipient product is ready touse.

[0099] The pre-manufactured sustained release excipient is preferablyfree-flowing and directly compressible. Accordingly, the excipient maybe mixed in the desired proportion with a therapeutically activemedicament and optional lubricant (dry granulation). Alternatively, allor part of the excipient may be subjected to a wet granulation with theactive ingredient and thereafter tableted. When the final product to bemanufactured is tablets, the complete mixture, in an amount sufficientto make a uniform batch of tablets, is then subjected to tableting in aconventional production scale tableting machine at normal compressionpressure, i.e. about 2000-1600 lbs/sq in. However, the mixture shouldnot be compressed to such a degree that there is subsequent difficultyin its hydration when exposed to gastric fluid.

[0100] One of the limitations of direct compression as a method oftablet manufacture is the size of the tablet. If the amount of active ishigh a pharmaceutical formulator may choose to wet granulate the activewith other excipients to attain a decent size tablet with the rightcompact strength. Usually the amount of filler/binder or excipientsneeded in wet granulation is less than that in direct compression sincethe process of wet granulation contributes to some extent toward thedesired physical properties of a tablet.

[0101] When the medicament is diltiazem, the average tablet size forround tablets is preferably about 300 mg to 750 mg and forcapsule-shaped tablets about 700 mg to 1000 mg.

[0102] The average particle size of the granulated excipient of thepresent invention preferably ranges from about 50 microns to about 400microns and preferably from about 185 microns to about 265 microns. Theparticle size of the granulation is not narrowly critical, the importantparameter being that the average particle size of the granules, mustpermit the formation of a directly compressible excipient which formspharmaceutically acceptable tablets. The desired tap and bulk densitiesof the granulation of the present invention are normally between fromabout 0.3 to about 0.8 g/ml, with an average density of from about 0.5to about 0.7 g/ml. For best results, the tablets formed from thegranulations of the present invention are from about 5 to about 20 kghardness. The average flow of the granulations prepared in accordancewith the present invention are preferably from about 25 to about 40g/sec. Tablets compacted using an instrumented rotary tablet machinehave been found to possess strength profiles which are largelyindependent of the inert saccharide component. Scanning electronphotomicrographs of largely tablet surfaces have provided qualitativeevidence of extensive plastic deformation on compaction, both at thetablet surface and across the fracture surface, and also show evidenceof surface pores through which initial solvent ingress and solutionegress may occur.

[0103] In certain embodiments of the invention, the tablet is coatedwith a sufficient amount of a hydrophobic polymer to render theformulation capable of further modifying the release of the medicament.The hydrophobic polymer which is included in the tablet coating may bethe same or different material as compared to the hydrophobic polymericmaterial which is optionally granulated with the sustained releaseexcipient.

[0104] In other embodiments of the present invention, the tablet coatingmay comprise an enteric coating material in addition to or instead ofthe hydrophobic polymer coating. Examples of suitable enteric polymersinclude cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, polyvinylacetate phthalate, methacrylic acid copolymer,shellac, hydroxypropylmethylcellulose succinate, cellulose acetatetrimellitate, and mixtures of any of the foregoing. An example of asuitable commercially available enteric material is available under thetrade name Eudragit™ L30D55.

[0105] In further embodiments, the dosage form may be coated with ahydrophilic coating in addition to or instead of the above-mentionedcoatings. An example of a suitable material which may be used for such ahydrophilic coating is hydroxypropylmethyl-cellulose (e.g., Opadry®commercially available from Colorcon, West Point, Pa.).

[0106] The coatings may be applied in any pharmaceutically acceptablemanner known to those skilled in the art. For example, in oneembodiment, the coating is applied via a fluidized bed or in a coatingpan. For example, the coated tablets may be dried, e.g., at about 60-70°C. for about 3-4 hours in a coating pan. The solvent for the hydrophobicpolymer or enteric coating may be organic, aqueous, or a mixture of anorganic and an aqueous solvent. The organic solvents may be, e.g.,isopropyl alcohol, ethanol, and the like, with or without water.

[0107] In additional embodiments of the present invention, a supportplatform is applied to the tablets manufactured in accordance with thepresent invention. Suitable support platforms are well known to thoseskilled in the art. An example of suitable support platform is setforth, e.g., in U.S. Pat. No. 4,839,177, hereby incorporated byreference. In that patent, the support platform partially coats thetablet, and consists of a polymeric material insoluble in aqueousliquids. The support platform may, for example, be designed to maintainits impermeability characteristics during the transfer of thetherapeutically active medicament. The support platform may be appliedto the tablets, e.g., via compression coating onto part of the tabletsurface, by spray coating the polymeric materials comprising the supportplatform onto all or part of the tablet surface, or by immersing thetablets in a solution of the polymeric materials.

[0108] The support platform may have a thickness of, e.g., about 2 mm ifapplied by compression, and about 10μ if applied via spray-coating orimmersion-coating. Generally, in embodiments of the invention wherein ahydrophobic polymer or enteric coating is applied to the tablets, thetablets are coated to a weight gain from about 1 to about 20%, and incertain embodiments preferably from about 5% to about 10%.

[0109] Materials useful in the hydrophobic coatings and supportplatforms of the present invention include derivatives of acrylic acid(such as esters of acrylic acid, methacrylic acid, and copolymersthereof) celluloses and derivatives thereof (such as ethylcellulose),polyvinylalcohols, and the like.

[0110] In certain embodiments of the present invention, the tablet coreincludes an additional dose of the medicament included in either thehydrophobic or enteric coating, or in an additional overcoating coatedon the outer surface of the tablet core (without the hydrophobic orenteric coating) or as a second coating layer coated on the surface ofthe base coating comprising the hydrophobic or enteric coating material.This may be desired when, for example, a loading dose of atherapeutically active agent is needed to provide therapeuticallyeffective blood levels of the active agent when the formulation is firstexposed to gastric fluid. The loading dose of medicament included in thecoating layer maybe, e.g., from about 10% to about 40% of the totalamount of medicament included in the formulation.

[0111] In preferred embodiments of the invention, the final formulationprovides bi-modal or multi-phasic plasma levels when the medicament isdiltiazem.

[0112] In preferred embodiments, when the medicament is diltiazem, theformulations of the invention provide a first time to peak plasmaconcentration (Tmax #1) of the diltiazem in about 4 to about 10 hoursafter oral administration of the dosage form to the patient. In certainpreferred embodiments, the first time to peak plasma concentrationoccurs from about 6 to about 8 hours after oral administration. Inpreferred embodiments, the maximum plasma concentration of diltiazem atthe first Tmax (Cmax #1) is from about 50 to about 100 ng/ml, peradministration of a 240 mg dosage of diltiazem in an oral sustainedrelease dosage form in accordance with the invention.

[0113] In further preferred embodiments of the invention, the sustainedrelease diltiazem formulations provide a second peak plasmaconcentration (Cmax #2) which occurs in about 10 to about 16 hours afteroral administration of the dosage form to the patient (Tmax #2). Incertain preferred embodiments, the second peak plasma concentration(Cmax #2) occurs in about 12 to about 14 hours after oral administrationof the dosage form to the patient (Tmax #2). In preferred embodiments,the maximum plasma concentration of diltiazem at Cmax #2 is from about60 to about 90 ng/ml, per 240 mg diltiazem administered over the 24 hourperiod.

[0114] In certain preferred embodiments, the sustained release diltiazemformulations provide a the W₅₀ of Cmax #1 (defined for purposes of thepresent invention as the width of the plasma concentration curve at 50%of the height of the first Cmax (Cmax #1), based on a trough taken atthe Cmin between Cmax #1 and Cmax #2) is from about 0.5 to about 4hours, preferably from about 1 to about 3 hours.

[0115] In certain preferred embodiments, the sustained release diltiazemformulations provide a W₅₀ of Cmax #2 (defined for purposes of thepresent invention as the width of the plasma concentration curve at 50%of the height of the second Cmax (Cmax #2), based on a the trough takenat the Cmin between Cmax #1 and Cmax #2) is from about 0.5 to about 8hours, preferably from about 2 to about 6 hours.

[0116] In certain preferred embodiments, the sustained release diltiazemformulations of the invention provide a ratio of Cmax #1 to Cmax #2 fromabout 0.5:1 to about 1.5:1; preferably from about 0.7:1 to about 1.2:1.

[0117] Based on the dosage of diltiazem in the sustained release oralformulations of the invention, one can easily determine the Cmax #1,Cmax #2, Tmax #1 and Tmax #2 for different dosages of diltiazem over a12 or 24 hour period.

[0118] In certain preferred embodiments of the invention when themedicament is oxybutynin, the formulation provides a time to peak plasmaconcentration (Tmax) of oxybutynin in about 5 to about 15 hours,preferably in about 8 to about 12 hours.

[0119] Examples of soluble to highly soluble medicaments which aresuitable for incorporation in the present invention includeantihistamines (e.g., azatadine maleate, brompheniramine maleate,carbinoxamine maleate, chlorpheniramine maleate, dexchlorpheniraminemaleate, diphenhydramine hydrochloride, doxylamine succinate,methdilazine hydrochloride, promethazine, trimeprazine tartrate,tripelennamine citrate, tripelennamine hydrochloride and triprolidinehydrochloride); antibiotics (e.g., penicillin v potassium, cloxacillinsodium, dicloxacillin sodium, nafcillin sodium, oxacillin sodium,carbenicillin indanyl sodium, oxytetracycline hydrochloride,tetracycline hydrochloride, clindamycin phosphate, clindamycinhydrochloride, clindamycin palmitate hcl, lincomycin hcl, novobiocinsodium, nitrofurantoin sodium, metronidazole hydrochloride);antituberculosis agents (e.g., isoniazid); cholinergic agents (e.g.,ambenonium chloride, bethanecol chloride, neostigmine bromide,pyridostigmine bromide); antimuscarinics (e.g., anisotropinemethylbromide, clidinium bromide, dicyclomine hydrochloride,glycopyrrolate, hexocyclium methylsulfate, homatropine methylbrornide,hyoscyamine sulphate, methantheline bromide, hyoscine hydrobromide,oxyphenonium bromide, propantheline bromide, tridihexethyl chloride);sympathomimetics (e.g., bitolterol mesylate, ephedrine, ephedrinehydrochloride, ephedrine sulphate, orciprenaline sulphate,phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride,ritodrine hydrochloride, salbutamol sulphate, terbutaline sulphate);sympatholytic agents (e.g., phenoxybenzamine hydrochloride);miscellaneous autonomic drugs (e.g., nicotine); iron preparations (e.g.,ferrous gluconate, ferrous sulphate); haemostatics (e.g., aminocaproicacid); cardiac drugs (e.g., acebutolol hydrochloride, disopyramidephosphate, flecainide acetate, procainamide hydrochloride, propranololhydrochloride, quinidine gluconate, timolol maleate, tocainidehydrochloride, verapamil hydrochloride); antihypertensive agents (e.g.,captopril, clonidine hydrochloride, hydralazine hydrochloride,mecamylamine hydrochloride, metoprolol tartrate); vasodilators (e.g.,papaverine hydrochloride); non-steroidal anti-inflammatory agents (e.g.,choline salicylate, magnesium salicylate, meclofenamate sodium, naproxensodium, tolmetin sodium); anticonvulsants (e.g., phenobarbital sodium,phenyloin sodium, troxidone, ethosuximide, valproate sodium);tranquilizers (e.g., acetophenazine maleate, chlorpromazinehydrochloride, fluphenazine hydrochloride, prochlorperazine edisylate,promethazine hydrochloride, thioridazine hydrochloride,trifluoroperazine hydrochloride, lithium citrate, molindonehydrochloride, thiothixine hydrochloride); stimulants (e.g.,benzamphetamine hydrochloride, dextroamphetamine sulphate,dextroamphetamine phosphate, diethylpropion hydrochloride, fenfluraminehydrochloride, methamphetamine hydrochloride, methylphenidatehydrochloride, phendimetrazine tartrate, phenmetrazine hydrochloride,caffeine citrate); barbiturates (e.g., amylobarbital sodium,butabarbital sodium, secobarbital sodium); sedatives (e.g., hydroxyzinehydrochloride, methprylon); expectorants (e.g., potassium iodide);antiemetics (e.g., benzaquinamide hydrochloride, metoclopropamidehydrochloride, trimethobenzamide hydrochloride); gastro-intestinal drugs(e.g., ranitidine hydrochloride); heavy metal antagonists (e.g.,penicillamine, penicillamine hydrochloride); antithyroid agents (e.g.,methimazole); genitourinary smooth muscle relaxants (e.g., flavoxatehydrochloride); vitamins (e.g., thiamine hydrochloride, ascorbic acid);unclassified agents (e.g., amantadine hydrochloride, colchicine,etidronate disodium, leucovorin calcium, methylene blue, potassiumchloride, pralidoxime chloride. This list is not meant to be exclusive.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0120] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-2 Effect of Drug:Gum Ratio in Formulation

[0121] In Example 1-2, sustained release excipients in accordance withthe present invention are first prepared, the medicament (in this casediltiazem) and the pH modifying agent (in this case being fumaric acid)being added subsequently, and the final mixture then being tableted.

[0122] The sustained release excipient is prepared by dry blending therequisite amounts of xanthan gum, locust bean gum, and dextrose in ahigh speed mixer/granulator for 3 minutes. While runningchoppers/impellers, water is added to the dry blended mixture, andgranulated for another 3 minutes. The granulation is then dried in afluid bed dryer to a LOD (loss on drying) of less than about 10% byweight (e.g., 4-7% LOD). The granulation is then milled using 20 meshscreens and dispensed into a granulator. The ingredients of thegranulations of Examples 1-2 are set forth in Table 1 below: TABLE 1PREPARATION OF SUSTAINED-RELEASE EXCIPIENT Component Amount (%) - Ex. 1Amount (%) - Ex. 2 1. Xanthan Gum 20 12 2. Locust Bean Gum 30 18 3.Dextrose 50 70 4. Water 30 25

[0123] Next, the desired amount of diltiazem, fumaric acid and asuitable amount of water are mixed for 5 minutes with an impeller typemixer to form a slurry. The slurry is then added to the sustainedrelease excipient over a 1 minute interval in the granulator, with theimpeller running on low speed. Next, the mixture is granulated for 2minutes with the chopper and impeller on high speed (additional waterand granulation time may be used to form proper granules). The resultantgranules are then dried in a fluid bed dryer until LOD is less than 5%and milled with hammer forward at 2000-3600 rpm. The milled granulationis then placed in a V-Blender with sodium lauryl sulfate and blended for10 minutes. A suitable tableting lubricant (Pruv®, sodium stearylfumarate, NF, commercially available from Penwest Pharmaceuticals Co. isadded, and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 768 mg. Theingredients of the tablets of Examples 1-2 are set forth in Table 2below: TABLE 2 TABLET FORMULATION - EXAMPLES 1-2 Component Amount (%)Amount (mg/tab) 1. Sustained-Release Excipient 52.1 400.0 2. Diltiazem31.3 240.0 3. Fumaric Acid 5.2 40.0 4. Sodium Laurel Sulfate 10.4 80.05. Pruv ® (Sodium Stearyl Fumarate) 1.0 8.0 6. Water* 27.5 0.0

[0124] The final tablets have a tablet weight of 768.0 mg and a hardnessof 15 Kp.

[0125] Dissolution tests were then carried out on the tablets ofExamples 1-2 in 900 ML water in an automated USP dissolution apparatus(Paddle type II, 100 rpm), and the amount of drug released was analyzedvia UV analysis. The in-vitro dissolution results are set forth in FIG.1 and in Table 3 below. TABLE 3 Time (hr) Ex. 1 (% dissolved) Ex. 2 (%dissolved) 0 0.0 0.0 1 13.4 8.3 2 19.0 12.4 4 28.4 18.4 8 40.9 29.0 1252.3 38.2 16 63.1 44.4 20 70.1 49.9 24 78.2 55.3

[0126] From the results provided in FIG. 1 and Table 3, it is evidentthat the rate of release of diltiazem is slower as the amount of gum inthe formulations is increased.

EXAMPLES 3-4 Effect of Gum:Dextrose Ratio

[0127] In Examples 3-4, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 3 and 4 areset forth in table 4 below: TABLE 4 Component Amount (%) - Ex. Amount(%) - Ex. 2 1 Xanthan Gum 12 20 2 Locust Bean Gum 18 30 3 Dextrose 70 504 Water* 25 35

[0128] Thereafter, diltiazem tablets are prepared as follows:

[0129] The desired amount of diltiazem, fumaric acid and the sustainedrelease excipient are placed in a granulator and mixed for 3 minutes atlow speed. Water is added over a 2 minute interval while the impeller isrunning at low speed (additional water and granulation time may be usedto form proper granules). The resultant granules are then dried in afluid bed dryer until LOD is less than 5% and milled with hammer forwardat 2000-3000 rpm using screen #0050. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co.) is added,and the mixture is blended for another 5 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 750 mg. Theingredients of the tablets of Examples 3-4 are set forth in Table 5below: TABLE 5 TABLET FORMULATION - EXAMPLES 3-4 Component Amount (%)Amount (mg/tab) 1. Sustained-Release Excipient 53.3 400.0 2. Diltiazem32.0 240.0 3. Fumaric Acid 8.0 60.0 4. Sodium Laurel Sulfate 5.3 40.0 5.Pruv ® (Sodium Stearyl Fumarate) 1.3 10.0 6. Water* 27.5 0.0

[0130] The final tablets have a tablet weight of 750.0 mg and a hardnessof 15 Kp

[0131] Dissolution tests were then carried out on the tablets ofExamples 3-4 in 250 ML buffer (ph 6) in an automated USP dissolutionapparatus (Paddle type III, 15CPM), and the amount of drug released wasanalyzed via UV analysis. The in-vitro dissolution results are set forthin FIG. 2 and in Table 6 below: TABLE 6 Time (hr) Ex. 3 (% dissolved)Ex. 4 (% dissolved) 0 0.0 0.0 1 20.1 14.3 3 36.5 25.2 8 64.7 45.5 1288.3 57.2 16 102.2 67.4 24 103.6 86.2

[0132] From the results provided in FIG. 2 and Table 6, it is evidentthat as the amount of gum relative to the amount of dextrose isincreased, a corresponding decrease in drug release is observed.

EXAMPLES 5-6 Effect of Surfactant Type

[0133] In Examples 5-6, a sustained release excipient is preparedaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 5 and 6 areset forth in table 7 below: TABLE 7 Component Amount (%) - Ex. 5-6 1Xanthan Gum 12 2 Locust Bean Gum 18 3 Dextrose 70 4 Water* 25

[0134] Thereafter, diltiazem tablets are prepared as follow:

[0135] The desired amount of diltiazem, fumaric acid and a suitableamount of water are mixed for 5 minutes with an impeller type mixer toform a slurry. The slurry is then added to the sustained releaseexcipient over a 1 minute interval in the granulator, with the impellerrunning on low speed. Next, the mixture is granulated for 2 minutes withthe chopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation of Example5 is then placed in a V-Blender with sodium lauryl sulfate, and themilled granulation of Example 6 is placed in a V-Blender with docusatesodium and blended for 10 minutes. A suitable tableting lubricant(Pruv®, sodium stearyl fumarate, NF, commercially available from PenwestPharmaceuticals Co. is then added to each example, and the mixtures areblended for another 3 minutes. The resultant granulations are thencompressed into tablets using a capsule shaped punch. This final mixtureis tableted to approximately 848 mg. The ingredients of the tablets ofExamples 5-6 are set forth in Table 8 below: TABLE 8 TABLETFORMULATION - EXAMPLES 5-6 Amount (%) Amount (%) Component (Ex. 5) (Ex.6) 1. Sustained-Release Excipient 47.2 47.2 2. Diltiazem 28.3 28.3 3.Fumaric Acid 14.2 14.2 4. Sodium Laurel Sulfate 9.4 N/A 5. DocusateSodium N/A 9.4 6. Pruv ® (Sodium Stearyl Fumarate) 0.9 0.9 7. Water*26.5 26.5 Amount Amount (mg/tab) (mg/tab) Component (Ex. 5) (Ex. 6) 1Sustained-Release Excipient 400.0 400.0 2 Diltiazem 240.0 240.0 3Fumaric Acid 120.0 120.0 4 Sodium Laurel Sulfate 80.0 N/A 5 DocusateSodium N/A 80.0 6 Pruv ® (Sodium Stearyl Fumarate) 8.0 8.0

[0136] The final tablets have a tablet weight of 848.0 mg. and ahardness of 15 Kp.

[0137] Dissolution tests were then carried out on the tablets ofExamples 1-2. The dissolution tests were conducted in 900 ML water in anautomated USP dissolution apparatus (Paddle type II, 100 rpm), and theamount of drug released was analyzed via UV analysis. The in-vitrodissolution results are set forth in FIG. 3 and in Table 9 below. TABLE9 Time (hr) Ex. 5 (% dissolved) Ex. 6 (% dissolved) 0 0.0 0.0 1 14.012.2 2 19.3 18.9 4 31.3 29.8 8 49.5 47.6 12 62.7 61.4 16 77.0 73.0 2088.5 83.5 24 98.6 89.2

[0138] From the results provided in FIG. 3 and Table 9, it is evidentthat the rate of release of diltiazem is similar for equivalent ratiosof sodium lauryl sulfate and docusate sodium.

[0139] However, the formulation did process better with sodium laurylsulfate.

EXAMPLES 7-8 Effect of Surfactant Level

[0140] In Examples 7-8, a sustained release excipient is preparedaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 7 and 8 areset forth in table 10 below: TABLE 10 Component Amount (%) - Ex. 7-8 1.Xanthan Gum 12 2. Locust Bean Gum 18 3. Dextrose 70 4. Water* 25

[0141] Thereafter, diltiazem tablets are prepared as follows:

[0142] The desired amount of diltiazem, fumaric acid and a suitableamount of water are mixed for 5 minutes with an impeller type mixer toform a slurry. The slurry is then added to sustained release excipientover a 1 minute interval in the granulator, with the impeller running onlow speed. Next, the mixture is granulated for 2 minutes with thechopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co. is thenadded, and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 768 mg. Theingredients of the tablets of Examples 7-8 are set forth in Table 11below: TABLE 11 TABLET FORMULATION - EXAMPLES 7-8 Amount (%) Amount (%)Component (Ex. 7) (Ex. 8) 1. Sustained-Release Excipient 52.1 54.9 2.Diltiazem 31.3 33.0 3. Fumaric Acid 5.2 5.5 4. Sodium Laurel Sulfate10.4 5.5 5. Pruv ® (Sodium Stearyl Fumarate) 1.0 1.1 6. Water* 27.5 27.5*Removed during processing Amount Amount (mg/tab) (mg/tab) Component(Ex. 7) (Ex. 8) 1. Sustained-Release Excipient 400.0 400.0 2. Diltiazem240.0 240.0 3. Fumaric Acid 40.0 40.0 4. Sodium Laurel Sulfate 80.0 40.05. Pruv ® Sodium Stearyl Fumarate 8.0 8.0

[0143] The final tablets of Example 7 have a tablet weight of 768.0 mg.and a hardness of 15 Kp.

[0144] The final tablets of Example 8 have a tablet weight of 728.0 mg.and a hardness of 15 Kp.

[0145] Dissolution tests were then carried out on the tablets ofExamples 7-8. The dissolution tests were conducted in 900 ML water in anautomated USP dissolution apparatus (Paddle type II, 100 rpm), and theamount of drug released was analyzed via UV analysis. The results areset forth in FIG. 4 and Table 12 below: TABLE 12 Time (hr) Ex. 7 (%Dissolved) Ex. 8 (% Dissolved) 0 0.0 0.0 1 13.4 18.5 2 19.0 28.2 4 28.440.1 8 40.9 56.1 12 52.3 67.6 16 63.1 77.7 20 70.1 83.8 24 78.2 90.5

[0146] From the results provided in FIG. 4 and Table 12, it is evidentthat the dissolution rate of diltiazem is inversely related to thesurfactant level.

EXAMPLES 9-10 Effect of Fumaric Acid Level

[0147] In Examples 9-10, a sustained release excipient is preparedaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 9 and 10 areset forth in table 13 below: TABLE 13 Component Amount (%) - Ex. 9-10 1.Xanthan Gum 12 2. Locust Bean Gum 18 3. Dextrose 70 4. Water* 25

[0148] Thereafter, diltiazem tablets are prepared as follows:

[0149] The desired amount of diltiazem, fumaric acid and a suitableamount of water are mixed for 5 minutes with an impeller type mixer toform a slurry. The slurry is then added to sustained release excipientover a 1 minute interval in the granulator, with the impeller running onlow speed. Next, the mixture is granulated for 2 minutes with thechopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co. is thenadded, and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 848 mg. Theingredients of the tablets of Examples 9-10 are set forth in Table 14below: TABLE 14 TABLET FORMULATION - EXAMPLES 9-10 Amount (%) Amount (%)Component (Ex. 9) (Ex. 10) 1. Sustained-Release Excipient 47.2 52.1 2.Diltiazem 28.3 31.3 3. Fumaric Acid 14.2 5.2 4. Sodium Laurel Sulfate9.4 10.4 5. Pruv ® (Sodium Stearyl Fumarate) 0.9 1.0  *Sodium StearylFumarate 6. Water* 26.5 26.5 * Removed during processing Amount Amount(mg/tab) (mg/tab) Component (Ex. 9) (Ex. 10) 1. Sustained-ReleaseExcipient 400.0 400.0 2. Diltiazem 240.0 240.0 3. Fumaric Acid 120.040.0 4. Sodium Laurel Sulfate 80.0 80.0 5. Pruv ®* 8.0 8.0

[0150] The final tablets in Example 9 have a weight of 848.0 mg. and ahardness of 15 Kp.

[0151] The final tablets in Example 10 have a weight of 768 mg. and ahardness of 15 Kp.

[0152] Dissolution tests were then carried out on the tablets ofExamples 9-10. The dissolution tests were conducted in 900 ML water inan automated USP dissolution apparatus (Paddle type II, 100 rpm), andthe amount of drug released was analyzed via UV analysis. The resultsare set forth in FIG. 5 and Table 15 below: TABLE 15 Time (hr) Ex. 9 (%Dissolved) Ex. 10 (% Dissolved) 0 0.0 0.0 1 14.0 13.4 2 19.3 19.0 4 31.328.4 8 49.5 40.9 12 62.7 52.3 16 77.0 63.1 20 88.5 70.1 24 98.6 78.2

[0153] From the results provided in FIG. 5 and Table 15, it is evidentthat by increasing the amount of fumaric acid in the formulation, therelease rate increases.

EXAMPLES 11-12 Extra-Granular Addition of Drug

[0154] In Examples 11-12, a sustained release excipient is preparedaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 11 and 12 areset forth in table 16 below: TABLE 16 Component Amount (%) - Ex.11-12 1. Xanthan Gum 12 2. Locust Bean Gum 18 3. Dextrose 70 4. Water*25

[0155] Thereafter, diltiazem tablets are prepared as follows:

[0156] In Example 11, the desired amount of diltiazem, fumaric acid anda suitable amount of water are mixed for 5 minutes with an impeller typemixer to form a slurry. The slurry is then added to sustained releaseexcipient over a 1 minute interval in the granulator, with the impellerrunning on low speed. Next, the mixture is granulated for 2 minutes withthe chopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co. is thenadded, and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 848 mg.

[0157] In Example 12, a portion of diltiazem, fumaric acid and asuitable amount of water are mixed for 5 minutes with an impeller typemixer to form a slurry. The slurry is then added to sustained releaseexcipient over a 1 minute interval in the granulator, with the impellerrunning on low speed. Next, the mixture is granulated for 2 minutes withthe chopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and the remainingamount of diltiazem and blended for 0.10 minutes. A suitable tabletinglubricant (Pruv®, sodium stearyl fumarate, NF, commercially availablefrom Penwest Pharmaceuticals Co. is then added, and the mixture isblended for another 3 minutes. The resultant granulation is thencompressed into tablets using a capsule shaped punch. This final mixtureis tableted to approximately 848 mg. The ingredients of the tablets ofExamples 11-12 are set forth in Table 17 below: TABLE 17 TABLETFORMULATION - EXAMPLES 11-12 Amount Amount Component (%) (Ex. 11) (%)(Ex. 12) 1. Sustained-Release Excipient 47.2 47.2 2. Diltiazem(granular) 28.3 18.4 3. Diltiazem (extragranular) N/A 9.9 4. FumaricAcid 14.2 14.2 5. Sodium Laurel Sulfate 9.4 9.4 6. Pruv ® (SodiumStearyl Fumarate) 0.9 0.9 7. Water* 26.5 25.0 *Removed during processingAmount Amount (mg/tab) (mg/tab) Component (Ex. 11) (Ex. 12) 1.Sustained-Release Excipient 400.0 400.0 2. Diltiazem (granular) 240.0156.0 3. Diltiazem (extragranular) N/A 84.0 4. Fumaric Acid 120.0 120.05. Sodium Laurel Sulfate 80.0 80.0 6. Pruv ® (Sodium Stearyl Fumarate)8.0 8.0

[0158] The final tablets of Example 11 have a weight of 848.0 mg. and ahardness of 15 Kp.

[0159] The final tablets of Example 12 have a weight of 848.0 mg. and ahardness of 15 Kp.

[0160] Dissolution tests were then carried out on the tablets ofExamples 11-12. The dissolution tests were conducted in 900 ML water inan automated USP dissolution apparatus (Paddle type II, 100 rpm), andthe amount of drug released was analyzed via UV analysis. The resultsare set forth in FIG. 6 and Table 18 below: TABLE 18 Time (hr) Ex. 11 (%Dissolved) Ex. 12 (% Dissolved) 0 0.0 0.0 1 14.2 32.6 2 19.3 35.5 4 31.348.7 8 49.5 66.4 12 62.7 78.5 16 77.0 85.2 20 88.5 89.2 24 98.6 94.6

[0161] From the results provided in FIG. 6 and Table 18, it is shownthat the addition of diltiazem extragranularly produces an initial burstof approximately 35%. It is evident that the addition of a percentage ofthe drug extra-granularly provides an initial rapid release, as alsodemonstrated by FIG. 7 which depicts the % release rate of diltiazemfrom the dosage forms of Examples 11 and 12 over time.

EXAMPLES 13-18 Effect of Coating tablets With Eudragit L30D55 w/NaOH(Methacrylic Acid Copolymer Aqueous Dispersion)

[0162] In Examples 13-18, a sustained release excipient is preparedaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 13-18 are setforth in table 19 below: TABLE 19 Component Amount (%) - Ex. 13-18 1.Xanthan Gum 12 2. Locust Bean Gum 18 3. Dextrose 70 4. Water* 25

[0163] Thereafter, diltiazem tablets are prepared as follows:

[0164] The desired amount of diltiazem, fumaric acid and the sustainedrelease excipient are mixed in a granulator for 3 minutes at low speed.A suitable amount of water is then added over a 2 minute interval withthe impeller running at low speed. The resultant slurry is thengranulated for 7.5 minutes with the chopper and impeller on high speed(additional water and granulation time may be used to form propergranules). The resultant granules are then dried in a fluid bed dryeruntil LOD is less than 5% and milled with hammer forward at 2000-3000rpm using screen #0050. The milled granulation is then placed in aV-Blender with sodium lauryl sulfate and blended for 10 minutes. Asuitable tableting lubricant (Pruv®, sodium stearyl fumarate, NF,commercially available from Penwest Pharmaceuticals Co. is then added,and the mixture is blended for another 5 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 750 mg.

[0165] The ingredients of the tablets of Examples 13-18 are set forth inTable 20 below: TABLE 20 TABLET FORMULATION - EXAMPLES 13-18 ComponentAmount (%) 1. Sustained-Release Excipient 53.3 2. Diltiazem (granular)32.0 3. Fumaric Acid 8.0 4. Sodium Laurel Sulfate 5.3 5 Pruv ® (SodiumStearyl Fumarate) 1.3 6. Water* 27.0 *Removed during processingComponent Amount (mg/tab) 1. Sustained-Release Excipient 400.0 2.Diltiazem (granular) 240.0 3. Fumaric Acid 60.0 4. Sodium Laurel Sulfate40.0 5. Pruv ® (Sodium Stearyl Fumarate) 10.0

[0166] The final tablets have a tablet weight of 750.0 mg. and ahardness of 15 Kp.

[0167] The core tablets were then coated with an aqueous dispersion ofEudragit L30D55 w/NaOH, e.g., to a weight gain of 3%, 5%, 7%, and 9%(Examples 15-18, respectively) based on the weight of the whole tablet.

[0168] The aqueous dispersion was prepared by the following procedure:

[0169] 1.0N sodium hydroxide solution is prepared by adding 4.0 g ofsodium hydroxide to 50 ml purified water in a volumetric flask andstirring for 5-15 minutes. Purified water is then added to the necessaryvolume and mixed again.

[0170] The talc suspension is prepared by slowly adding 9.31 g triethylcitrate to 202.54 g purified water while stirring. While continuing tostir, 22.2 g talc is added to the container over a 3 minute interval.The container is stirred until a suspension is formed.

[0171] Eudragit suspension is then prepared by passing the Eudragitthrough a #40 mesh sieve and weighing out 294.52 g. Using a dropper,1.78 g of 1.0N sodium hydroxide solution is added to the Eudragit whilestirring. The mixture is stirred for 30-60 minutes.

[0172] While stirring the Eudragit suspension, the talc suspension isadded over a 5 minute period and stirred for 30-60 minutes.

[0173] Dissolution tests were carried out on the tablets of Examples13-18. The dissolution tests were conducted in 250 ML buffer (ph 6) inan automated USP dissolution apparatus (Paddle type III, 15 CPM), andthe amount of drug released was analyzed via UV analysis. The resultsare set forth in FIG. 8 and Table 21 below: TABLE 21 Time Ex. 13 Ex. 14Ex. 15 (hr) Lot A (no coating) Lot B (no coating) Lot A (3% coating)  00.0 0.0 0.0  1 18.4 18.0 5.4  3 32.6 32.8 16.0  8 59.8 60.2 48.9 12 80.577.9 68.2 16 92.3 93.9 89.6 24 93.7 98.4 99.0 Time Ex. 16 Ex. 17 Ex. 18(hr) Lot B (coating 5%) Lot B (coating 7%) Lot B (coating 9%)  0 0.0 0.00.0  1 1.9 0.4 0.4  3 13.8 11.1 8.9  8 44.1 36.3 27.5 12 63.4 54.4 41.816 82.4 77.7 56.8 24 98.3 99.6 84.6

[0174] From the results provided in FIG. 8 and Table 21, it is evidentthat as the amount (by weight) of the coating increases, the releaserate decreases.

EXAMPLES 19-20 Effect of Coating Tablets With EudragitRS30D/RL30D(50/50) (Ammonio-methacrylic Acid Copolymer AqueousDispersion)

[0175] In Examples 19-20, a sustained release excipient is preparedaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 19 and 20 areset forth in table 22 below: TABLE 22 Component Amount (%) - Ex.19-20 1. Xanthan Gum 12 2. Locust Bean Gum 18 3. Dextrose 70 4. Water*25

[0176] Thereafter, diltiazem tablets are prepared as follows:

[0177] The desired amount of diltiazem, fumaric acid and the sustainedrelease excipient are mixed in a granulator for 3 minutes at low speed.A suitable amount of water is then added over a 2 minute interval withthe impeller running at low speed. The resultant slurry is thengranulated for 6 minutes with the chopper and impeller on high speed(additional water and granulation time may be used to form propergranules). The resultant granules are then dried in a fluid bed dryeruntil LOD is less than 5% and milled with hammer forward at 2000-3000rpm using screen #0050. The milled granulation is then placed in aV-Blender with sodium lauryl sulfate and blended for 10 minutes. Asuitable tableting lubricant (Pruv®, sodium stearyl fumarate, NF,commercially available from Penwest Pharmaceuticals Co. is then added,and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 50 mg.

[0178] The ingredients of the tablets of Examples 19-20 are set forth inFIG. 9 and Table 23 below: TABLE 23 TABLET FORMULATION - EXAMPLES 19-20Component Amount (%) Amount (mg/tb) 1. Sustained-Release Excipient 53.3400.0 2. Diltiazem (granular) 32.0 240.0 3. Fumaric Acid 8.0 60.0 4.Sodium Laurel Sulfate 5.3 40.0 5. Pruv ® (Sodium Stearyl Fumarate) 1.310.0 6. Water* 27.0 0.0

[0179] The final tablets have a weight of 750.0 mg. and a hardness of Kp15.

[0180] The core tablet was then coated with an aqueous dispersion ofEudragit RS30D/RL30D(50/50) to a weight gain of 8%, based on the weightof the whole tablet.

[0181] The aqueous dispersion was prepared by the following procedure:

[0182] The Eudragit RS/RL suspension is prepared by mixing 100 g ofEudragit RS with 100 g of Eudragit RL.

[0183] Talc suspension is prepared by slowly adding 12.0 g triethylcitrate to 338.0 g purified water while stirring. While continuing tostir, 50.0 g talc is added to the container over a 3 minute interval.The container is stirred until a suspension is formed.

[0184] While stirring the Eudragit suspension, the talc suspension isthen added over a 5 minute period. The resultant mixture is stirred for30-60 minutes and screened through a 40 mesh sieve.

[0185] Dissolution tests were carried out on the tablets of Examples19-20. The dissolution tests were conducted in 900 ML of 0.1N HCL in anautomated USP dissolution apparatus (Paddle type II, 100 rpm), and theamount of drug released was analyzed via UV analysis. The results areset forth in FIG. 9 and Table 24 below: TABLE 24 Time (hr) Ex. 19 (8%coating) Ex. 20 (No coating) 0 0.0 0.0 1 21.5 0.5 3 41.3 11.6 5 55.924.4 8 74.3 46.4 10 84.8 57.5 12 91.9 64.9 14 95.1 72.2 16 96.2 77.6 2096.0 87.5 24 96.1 91.3

[0186] From the results provided in FIG. 9 and Table 24, it is evidentthat the coating-decreased the release rate.

EXAMPLES 21-23 Effect of Coating Tablets With Ethylcellulose

[0187] In Examples 21-23, a sustained release excipient is preparedaccordance with the procedure set forth in Examples 1 and 2. Theingredients of the sustained release excipient of Examples 21-23 are setforth in table 25 below: TABLE 25 Component Amount (%) - Ex. 21-23 1.Xanthan Gum 12 2. Locust Bean Gum 18 3. Dextrose 70 4. Water* 25

[0188] Thereafter, diltiazem tablets are prepared as follows:

[0189] The desired amount of diltiazem, fumaric acid and the sustainedrelease excipient are mixed in a granulator for 3 minutes at low speed.A suitable amount of water is then added over a 2 minute interval withthe impeller running at low speed. The resultant slurry is thengranulated for 3 minutes with the chopper and impaler on high speed(additional water and granulation time may be used to form propergranules). The resultant granules are then dried in a fluid bed dryeruntil LOD is less than 5% and milled with hammer forward at 2000-3000rpm using screen #0050. The milled granulation is then placed in aV-Blender with sodium lauryl sulfate and blended for 10 minutes. Asuitable tableting lubricant (Pruv®, sodium stearyl Fumarate, NF,commercially available from Penwest Pharmaceuticals Co. is then added,and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 750 mg.

[0190] The ingredients of the tablets of Examples 21-23 are set forth inTable 26 below: TABLE 26 TABLET FORMULATION - EXAMPLES 21-23 ComponentAmount (%) Amount (mg/tab) 1. Sustained-Release Excipient 53.3 400.0 2.Diltiazem (granular) 32.0 240.0 3. Fumaric Acid 8.0 60.0 4. SodiumLaurel Sulfate 5.3 40.0 5. Pruv ® (Sodium Stearyl Fumarate) 1.3 10.0 6.Water* 29.0 0.0

[0191] The final tablets have a tablet weight of 750.0 mg. and ahardness of 15 Kp.

[0192] The core tablet was then coated with an aqueous dispersion ofEthylcellulose/Opadry (80/20) to a weight gain of 4% and 6% (Examples 22and 23, respectively) based on the whole weight of the tablet. Theaqueous dispersion was prepared by the following procedure:

[0193] First, 60 g of Opadry is mixed with 340 g of water in a suitablecontainer. While continuing to mix, 944 g Ethylcellulose is added to theOpadry dispersion. The resultant mixture is stirred for 30-60 minutes.

[0194] Dissolution tests were then carried out on the tablets ofExamples 1-2. The dissolution tests are conducted in 250 ML of buffer(ph 6) in an automated USP dissolution apparatus (Paddle type m, 15CPM), and the amount of drug released was analyzed via UV analysis.

[0195] The results are set forth in FIG. 10 and Table 21 below: TABLE 27Ex. 21 Ex. 22 Ex. 23 Time (hr) (No Coating) (4% Coating) (6% Coating) 00.0 0.0 0.0 1 8.8 4.1 0.5 3 39.1 29.8 2.6 8 69.0 61.2 58.2 12 85.1 86.795.5 16 106.6 99.8 101.3 24 107.0 101.9 101.5

[0196] From the results provided in FIG. 10 and Table 27, it is evidentthat as the amount of coating increased, the release rate decreased.

EXAMPLES 24-25 Effect of Excipient Addition Outside Granulation

[0197] In Examples 24-25, a sustained release excipient is prepared inaccordance with the procedure in Examples 1 and 2. The ingredients ofthe sustained release excipient of Examples 24 and 25 are set forth inTable 28 below: TABLE 28 Component Amount (%) Ex. 25 Amount (%) Ex.26 1. xanthan Gum 12 12 2. Locust Bean Gum 18 18 3. Dextrose 70 70 4.Water* 25 25

[0198] Next, tablets were manufactured in accordance with theingredients of Table 29 and the procedure that follows: TABLE 29 (%)mg/tab (%) Component Ex. 24 Ex. 24 Ex. 25 mg/tabEx25 1. SustainedRelease 49.2 400.0 53.3 400.0  Excipient 2. Diltiazem HCL 19.2 156.032.0 240.0  (Intragranular) 3. Diltiazem HCI 10.3 84.0 N/A N/A  (Extragranular) 4. Fumaric Acid 14.8 120.0 8.0 60.0 5. Surfactant (SLS) 4.940.0 5.3 40.0 6. Sodium Stearyl 1.6 13.0 1.3 10.0  Fumarate, NF 7.Water* 27.0 0.0 27.0 0.0

[0199] The final tablets of Example 24 have a tablet weight of 813.0 mg.and a hardness of 15 Kp.

[0200] The final tablets of Example 25 have a tablet weight of 750.0 mg.and a hardness of 15 Kp.

[0201] The procedure for preparing the formulations of Examples 24-25 isa s follows:

[0202] The desired amount of (1), (2), and (4) are dispensed into agranulator and mixed for 3 minutes at low speed; while running theimpeller at low speed, (7) is added over a 2 minute interval; themixture is granulated for 7.5 minutes with the chopper and the impelleron high speed (additional water and granulation time may be used to formproper granules); the granulated mixture is dried in a fluid bed dryeruntil the LOD is less than 5%; the dried

[0203] granulation is milled with the hammer forward at 2000-3000 rpmusing screen #0050; the milled granulation and (5) or (3&5) are placedin a V-Blender and blended for 10 minutes; (6) is added to the V-Blenderand blended for 5 minutes. The final mixture is compressed into tabletsusing a capsule shaped punch.

[0204] The Eudragit® L30D55 w/NaOH Coating Dispersion was prepared asfollows:

[0205] A. 1.0N Sodium Hydroxide solution was prepared by adding 4.0 g ofSodium Hydroxide to a 100 ml volumetric flask; then 50 ml of Purifiedwater and a magnetic stir bar were added into the flask and the contentsof the flask were mixed for 5-15 minutes; the stir bar was removed andthe volume was Q.S. and mixed.

[0206] B. Talc suspension was prepared by weighing 202.54 g of Purifiedwater in a suitable container; 9.31 g of Triethyl Citrate was slowlyadded while the Purified water was stirred; then 22.22 g of Talc wasadded over a 2 minute interval to the container while the mixture wasstirred (the mixture was stirred until a suspension formed).

[0207] C. Eudragit® L30D55 Suspension was prepared by passing theEudragit® L30D55 through a #40 mesh sieve; 294.52 g of sieved Eudragit®L30D55 was weighed and placed into a suitable container; using adropper, 3.56 g of the 1.0N Sodium Hydroxide solution (Step A) was addedwhile the mixture was stirred; the mixture was stirred for 30-60minutes.

[0208] D. The final Coating Suspension was prepared by stirring theEudragit® L30D55 Suspension (Step C) while Talc suspension (step B) wasadded over a 5 minute period; the mixture was stirred for 30-60 minutes.

[0209] The tablets were coated for a weight gain of 4% based on thewhole weight of the tablet. The tablets were encapsulated by placing thecoated tablets into clear gelatin capsules.

Plasma Profile of Example 24

[0210] In-vivo studies were performed with the tablet of Example 24using a two way randomized, open label crossover design in healthyvolunteers, 12 subjects for each, and they were dosed in the fastedstate and compared with CARDIZEM CD®. The results are set forth in FIG.11 and in Tablet 30 below: TABLE 30 Time (hours) Ex. 24 Fasted (ng/ml)Cardizem-CD Fasted (ng/ml) 0 0.00 0.00 1 0.65 0.00 2 4.72 0.00 4 31.0219.65 6 62.45 83.08 7 63.27 60.98 8 65.45 50.79 9 64.20 42.52 10 65.3938.43 12 77.30 42.56 14 82.86 52.58 15 81.91 56.40 16 80.17 57.48 1870.09 57.73 20 57.59 51.97 24 42.21 43.48 30 24.82 28.73 36 10.97 12.848 2.55 3.78

Ratio

[0211] The ratio of the area are under the curve between Example 24 andCARDIZEM CD® 240 mg was 1.16:1. The ratio of the average Cmax betweenExample 25 and Cardizem CD 240 mg was 1.16:1.

Outcome

[0212]FIG. 11 and Example 24 demonstrated a Bi-Modal plasma levelin-vivo, the CARDIZEM CD® also demonstrated Bi-Modal plasma levels bythe mixture of two differently processed bead formulations.

Plasma Profile of Example 25

[0213] In-vivo studies were performed with the tablets of Example 25using a two way randomized, open label crossover design in healthyvolunteers, 12 subjects for each and they were dosed in the fasted stateand compared with CARDIZEM CD®. The results set forth in FIG. 12 and inTable 31 below: TABLE 31 Time (hours) EXAMPLE Fasted (ng\ml) Cardizem-CDFasted (ng\ml) 0 0.00 0.00 1 0.30 0.05 2 6.55 0.40 4 35.43 5.48 6 77.7166.02 7 76.91 58.31 8 70.88 47.29 9 66.18 39.31 10 64.98 35.51 12 71.9038.55 14 65.48 41.66 15 62.72 47.32 16 60.60 49.73 18 48.87 51.16 2038.95 45.75 24 33.10 41.44 30 20.93 28.40 36 10.14 14.88 48 2.52 4.00

[0214] The ratio of the area under the curve between Example 25 andCardizem CD 240 mg. was 1.16:1. The ratio of the average Cmax betweenExample 25 and Cardizem CD 240 mg.

Outcome

[0215]FIG. 12 and Example 25 demonstrated a Bi-Modal plasma levelin-vivo, CARDIZEM CD® also demonstrated Bi-Modal plasma levels by themixture of two differently processed bead formulations.

EXAMPLES 26 AND 27 Effect of Different Excipients

[0216] In Examples 26 and 27, a sustained release excipient is preparedin accordance with the procedure set froth in Examples 1 and 3. Theingredients of the sustained release excipient of Examples 25 and 26 areset forth in Table 32 below: TABLE 32 Component (%) Example 26 Example27 1. Xanthan Gum 12 25 2. Locust Bean Gum 18 25 3. Calcium Sulfate N/A10 4. Ethyl Cellulose N/A 5 5. Dextrose 70 35 6. Water* 25 N/A 7.Ethanol* N/A 20

Formulation Table 33

[0217] Thereafter, diltiazem tablets ate prepared as follows:

[0218] The desired amount of diltiazem, fumaric acid and the sustainedrelease excipient are placed in a granulator and mixed for 3 minutes atlow speed. Water is added over a 2 minute interval while the impeller isrunning at low speed (additional water and granulation time may be usedto form proper granules). The resultant granules are then dried in afluid bed dryer until LOD is less than %5 and milled with hammer forwardat 2000-3000 rpm using screen #0050. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co. is added,and the mixture is blended for another 5 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 750 mg. Theingredients of the tablets of Examples 26 and 27 are set forth in Table33 below: TABLE 33 Ex. 26 Ex. 27 Component Ex. 26% mg/tab Ex. 27% mg/tab1 Sustained Release Excipient 53.3 400.0 53.3 400.0 2 Diltiazem HCI 32.0240.0 32.0 240.0 3 Fumaric Acid 8.0 60.0 8.0 60.0 4 Surfactant (SLS) 5.340.0 5.3 40.0 5 Sodium Stearyl Fumarate 1.3 0.0 30.0 0.0 6 *Water 27.00.0 30.0 0.0

[0219] The final tablets in Example 26 have a tablet weight of 750.0 mg.and a hardness of 15 Kp.

[0220] The final tablets in Example 27 have a tablet weight of 750.0 mg.and a hardness of 15 Kp.

[0221] Dissolution tests were then carried out on the tablets of Example26 and 27 in 250 ML buffer (pH 6) in an automated USP dissolutionapparatus (Paddle type III, 15CPM), and the amount of drug released wasanalyzed via UV analysis. The in-vitro are set forth in FIG. 13 andTable 34 below: TABLE 34 Time (hours) Example 25 (% dissolved) Example26 (% dissolved) 0.0 0.0 0.0 1.0 18.4 12.6 3.0 32.6 23.9 8.0 59.8 45.912.0 80.5 60.3 16.0 92.3 71.8 24.0 93.7 91.4

Conclusion

[0222] Example 26 had a dissolution profile that was slower than Example25.

Outcome

[0223] Dissolution rate can be modified by using different grades ofexcipient.

EXAMPLES 28-29 Effect of Gum:Drug Ratio in Formulation

[0224] In Example 28-29, sustained release excipients in accordance withthe present invention are first prepared, the medicament (in this caseoxybutynin) and the pH modifying agent (in this case being succinicacid) being added subsequently, and the final mixture then beingtableted.

[0225] The sustained release excipient is prepared by dispensing xanthangum, locust bean gum dextrose and calcium sulfate into a high shearmixer/granulator, dispensing ethyl cellulose into a vessel containingethanol, dispensing the ethyl cellulose/ethanol mixture into the xanthangum, locust bean gum, dextrose, calcium sulfate mixture and granulatingto form proper granules, drying the mixture in a fluid bed dryer andmilling the dried material to form proper granules. The ingredients ofthe sustained-release excipient of Examples 28-29 are set forth in Table35 below: TABLE 35 PREPARATION OF SUSTAINED-RELEASE EXCIPIENT ComponentAmount (%) - Ex. 28 Amount (%) - Ex. 29 1. Xanthan Gum 20 15 2. LocustBean Gum 30 15 3. Dextrose 40 60 4. Calcium Sulfate 10 10 5. Water*20-30 20-30

[0226] Next, the desired amount of oxybutynin and sodium stearylfumarate are screened through a 25 mesh sieve, the screened oxybutyninand sustained release excipient are dispensed into a V-blender andblended for 10 minutes, the screened sodium stearyl fumarate is addedinto the blended mixture of oxybutynin and sustained-release excipientand blended for an additional 5 minutes, the final blended end productis then compressed into tablets using a {fraction (5/16)}″ round shapedtooling. This final mixture is tableted to approximately 179.4 mg. Theingredients of the tablets of Examples 28-29 are set forth in Tables 36and 37 below: TABLE 36 TABLET FORMULATION - EXAMPLE 28 Component Amount(%) Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2.Oxybutynin HCL 5.6 10.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight179.4 Hardness (Kp) 5

[0227] TABLE 37 TABLET FORMULATION - EXAMPLE 29 Component Amount (%)Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. OxybutyninHCL 5.6 10.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight 179.4Hardness (Kp) 5

[0228] The final tablets have a tablet weight of 179.4.0 mg and ahardness of 5 Kp.

[0229] Dissolution tests were then carried out on the tablets ofExamples 28-29. The in-vitro dissolution results are set forth in Table38 below. TABLE 38 Time (hr) Ex. 28 (% dissolved) Ex. 29 (% dissolved)0.0 0.0 0.0 2.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.512.0 108.7 88.9 20.0 108.7 92.8

[0230] The formulation of Example 28 has a drug:gum ratio of 1:5 and theformulation of Example 29 has a drug:gum ratio of 1:8.3. From theresults provided in Table 38, it is evident that the rate of release ofoxybutynin is slower as the drug:gum ratio in the formulations isincreased.

EXAMPLES 30-31 Effect of Gum:Dextrose Ratio

[0231] In Examples 30-31, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 28 and 29. Theingredients of the sustained release excipient of Examples 30 and 31 areset forth in Table 39 below: TABLE 39 Component Amount (%) Ex. 30 Amount(%) Ex. 31 1 Xanthan Gum 20 15 2 Locust Bean Gum 30 15 3 Dextrose 40 604 Calcium Sulfate 10 10 5 Water* 20-30 20-30

[0232] Thereafter, oxybutynin tablets are prepared as follows:

[0233] The desired amount of oxybutynin and sodium stearyl fumarate arescreened through a mesh sieve, the screened oxybutynin and sustainedrelease excipient are dispensed into a V-blender and blended for 10minutes, the screened sodium stearyl fumarate is added into the blendedmixture of oxybutynin and sustained-release excipient and blended for anadditional 5 minutes, the final blended end product is then compressedinto tablets using a {fraction (5/16)}″ round shaped tooling. This finalmixture is tableted to approximately 179.4 mg. The ingredients of thetablets of Examples 30-31 are set forth in Tables 40 and 41 below: TABLE40 TABLET FORMULATION - EXAMPLE 30 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. Oxybutynin HCL 5.610.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight 179.4 Hardness(Kp) 5

[0234] TABLE 41 TABLET FORMULATION - EXAMPLE 31 Component Amount (%)Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. OxybutyninHCL 5.6 10.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight 179.4Hardness (Kp) 5

[0235] The final tablets have a tablet weight of 17940 mg and a hardnessof 5 Kp.

[0236] Dissolution tests were then carried out on the tablets ofExamples 30-31. The in-vitro dissolution results are set forth in Table38 below. TABLE 42 Time (hr) Ex. 30 (% dissolved) Ex. 31 (% dissolved)0.0 0.0 0.0 2.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.512.0 108.7 88.9 20.0 108.7 92.8

[0237] From the results provided in Table 42, it is evident that as theamount of gum relative to the amount of dextrose is increased, acorresponding decrease in release of oxybutynin is observed.

EXAMPLES 32-35 Effect of Succinic Acid

[0238] In Examples 32-33, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 28 and 29. Theingredients of the sustained release excipient of Examples 32 and 33 areset forth in Table 43 below: TABLE 43 Component Amount (%) - Ex. 32-33 1Xanthan Gum 25 2 Locust Bean Gum 25 3 Dextrose 35 4 Calcium Sulfate 10 5Ethyl Cellulose 5 6 Water* 20-30

[0239] Thereafter, oxybutynin tablets are prepared as follows:

[0240] The desired amount of succinic acid, oxybutynin and sodiumstearyl fumarate are screened through a 25 mesh sieve, the screenedsuccinic acid and sustained release excipient are dispensed into aV-blender and blended for 10 minutes, the screened oxybutynin is addedinto the blended mixture of succinic acid and sustained-releaseexcipient and blended for an additional 5 minutes, the screened sodiumstearyl fumarate is added to the blended mixture of oxybutynin, succinicacid and sustained-release excipient and blended for an additional 5minutes, the final blended end product is then compressed into tabletsusing a {fraction (5/16)}″ round shaped tooling. The final mixture ofExample 32 is tableted to approximately 251.0 mg and the final mixtureof Example 33 is tableted to approximately 296.0 mg. The ingredients inExamples 32-33 are set forth in Tables 44 and 45 below: TABLE 44 TABLETFORMULATION - EXAMPLE 32 Component Amount (%) Amount (mg/tab) 1.Sustained Release Excipient 93.2 234.0 2. Succinic Acid N/A N/A 3.Oxybutynin HCL 6 15.0 4. Sodium Stearyl Fumarate 0.8 2.0 Tablet weight251 Hardness (Kp) 8

[0241] The final tablets have a tablet weight of 251.0 mg and a hardnessof 8 Kp. TABLE 45 TABLET FORMULATION - EXAMPLE 33 Component Amount (%)Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. SuccinicAcid 15.2 45.0 2. Oxybutynin HCL 5.1 15.0 3. Sodium Stearyl Fumarate 0.72.0 Tablet weight 296.0 Hardness (Kp) 8

[0242] The final tablets have a tablet weight of 296.0 mg and a hardnessof 8 Kp.

[0243] Dissolution tests were then carried out on the tablets ofExamples 32-33. The in-vitro dissolution results are set forth in Table46 below: TABLE 46 Ex. 32 (% dissolved) Ex. 33 (% dissolved) Time (hr)(0%) (15%) 0.0 0.0 0.0 2.0 1.3 8.9 4.0 2.1 12.9 6.0 4.7 24.0 8.0 11.334.0 12.0 25.9 44.0 20.0 43.9 59.5

[0244] From the results provided in Table 46, it is evident that theaddition of Succinic Acid acids in the solubility of the drug substance,therefore, increasing the release rate.

[0245] In Examples 34-35, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 28 and 29. Theingredients of the sustained release excipient of Examples 34 and 35 areset forth in Table 47 below: TABLE 47 Component Amount (%) - Ex. 34-35 1Xanthan Gum 25 2 Locust Bean Gum 25 3 Dextrose 35 4 Calcium Sulfate 10 5Ethyl Cellulose 5 6 Water* 20-30

[0246] Thereafter, oxybutynin tablets are prepared as follows:

[0247] The desired amount of sustained-release excipient, succinic acid,and oxybutynin are dispensed into a granulator. They are dry mixed for 3minutes with the impeller at low speed with the chopper blade in the offposition. Water is added over a 1 minute interval, then the mixture isgranulated at high speed for 3 minutes (additional water and granulationtime may be used to form proper granules). Next, the mixture is dried ina fluid bed dryer until the LOD is less than 5%. The dried granulationis milled with the blade forward at 2000-3000 rpm. The milledgranulation and sodium stearyl fumarate are placed into a V-Blender andblended for 10 minutes. The blended mixture is then compressed intotablets using a {fraction (5/16)}″ round shaped tooling. The finalmixture of Example 34 is tableted to approximately 296.0 mg and thefinal mixture of Example 35 is tableted to approximately 266.0 mg. Theingredients in Examples 34-35 are set forth in Tables 48 and 49 below:TABLE 48 TABLET FORMULATION - EXAMPLE 34 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 79.1 234.0 2. Succinic Acid 15.245.0 3. Oxybutynin HCL 5.1 15.0 4. Sodium Stearyl Fumarate 0.7 2.0 5.Water* 30-45 N/A Tablet weight 296.0 Hardness (Kp) 8

[0248] The final tablets have a tablet weight of 296.0.0 mg and ahardness of 8 Kp. TABLE 49 TABLET FORMULATION - EXAMPLE 35 ComponentAmount (%) Amount (mg/tab) 1. Sustained Release Excipient 88.0 234.0 2.Succinic Acid 5.6 15.0 3. Oxybutynin HCL 5.6 15.0 4. Sodium StearylFumarate 0.8 2.0 5. Water* 30-45 N/A Tablet weight 266.0 Hardness (Kp) 8

[0249] The final tablets have a tablet weight of 266.0 mg and a hardnessof 8 Kp.

[0250] Dissolution tests were then carried out on the tablets ofExamples 34-35. The in-vitro dissolution results are set forth in Table50 below: TABLE 50 Ex. 32 (% dissolved) Ex. 33 (% dissolved) Time (hr)(15%) (6%) 0.0 0.0 0.0 2.0 9.2 5.8 4.0 13.7 7.9 6.0 21.2 11.7 8.0 34.223.4 12.0 49.1 37.4 18.0 63.9 57.5

[0251] From the results provided in Table 50, it is evident that thehigher the amount of Succinic Acid in the formulation the faster therelease rate.

EXAMPLE 36 Effect of Coating Tablets With Ethylcellulose(Surelease®)/Opadry® (80/20) Aqueous Dispersion

[0252] The procedure for preparing the Ethylcellulose/Opadry® coating isas follows:

[0253] First, weigh 340 g of Water in a suitable container, add 60 g ofOpadry®, to the water while mixing. Continue to mix. While mixing theOpadry® dispersion, add 933 g of Ethylcellulose dispersion (Surelease®)and allow to stir for 30-60 minutes. The final dispersion is used tocoat the tablets for a weight gain of 3-5% based on the whole weight ofthe tablet.

[0254] In Example 36, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 28 and 29. Theingredients of the sustained release excipient of Example 36 is setforth in Table 51 below: TABLE 51 Component Amount (%) - Ex. 36 1.Xanthan Gum 25 2. Locust Bean Gum 25 3. Dextrose 35 4. Calcium Sulfate10 5. Ethyl Cellulose 5 6. Water* 20-30

[0255] Thereafter, oxybutynin tablets are prepared as follows:

[0256] The desired amount of sustained-release excipient, succinic acid,and oxybutynin are dispensed into a granulator. They are dry mixed for 3minutes with the impeller at low speed with the chopper blade in the offposition. Water is added over a 1 minute interval, then the mixture isgranulated at high speed for 3 minutes (additional water and granulationtime may be used to form proper granules). Next, the mixture is dried ina fluid bed dryer until the LOD is less than 5%. The dried granulationis milled with the blade forward at 2000-3000 rpm. The milledgranulation and sodium stearyl fumarate are placed into a V-Blender andblended for 10 minutes. The blended mixture is then compressed intotablets using a {fraction (5/16)}″ round shaped tooling. The finalmixture of Example 36 is tableted to approximately 296.0 mg. Theingredients in Examples 36 is set forth in Table 52 below: TABLE 52TABLET FORMULATION - EXAMPLE 36 Component Amount (%) Amount (mg/tab) 1.Sustained Release Excipient 79.1 234.0 2. Succinic Acid 15.2 45.0 3.Oxybutynin HCL 5.1 15.0 4. Sodium Stearyl Fumarate 0.7 2.0 5. Water*30-45 N/A Tablet weight 296.0 Hardness (Kp) 8

[0257] The final tablets have a tablet weight of 296.0.0 mg and ahardness of 8 Kp.

[0258] Dissolution tests were then carried out on the tablets of Example36. The in-vitro dissolution results are set forth in Table 53 below:TABLE 53 Time (hr) Ex. 1 Ex. 2 Ex. 3 0.0 0.0 0.0 0.0 2.0 26.8 7.1 1.74.0 32.1 10.3 2.8 6.0 35.8 14.9 5.5 8.0 40.1 20.2 9.0 12.0 54.2 27.415.1 20.0 72.2 53.2 32.7

[0259] From the results provided in Table 53, it is evident that as theamount, by weight of coating increased, the release rate decreased.

EXAMPLE 37 Effect of Fumaric Acid

[0260] In Example 37, a sustained-release excipient is prepared inaccordance with the procedure set forth in Examples 28-29. Theingredients of the sustained-release excipient of Example 37 is setforth in Table 54 below: TABLE 54 Component Amount (%) - Ex. 37 1Xanthan Gum 25 2 Locust Bean Gum 25 3 Dextrose 35 4 Calcium Sulfate 10 5Ethyl Cellulose  5 6 Water* 20-30

[0261] TABLET FORMULATION - EXAMPLE 37 Component Amount (mg/tab) 1.Sustained Release Excipient 166.7 2. Oxybutynin HCL 15 3. Fumaric Acid30 4. Pruv ® 2 Total (core only) 213.7

[0262] The final tablets have a tablet weight of 213.7 mg.

[0263] Dissolution tests were then carried out on the tablets of Example37 in comparison to Ditropan XL. The in-vitro dissolution results areset forth in Table 55 below: TABLE 55 % Dissolved/Released Time (hr)Ditropan XL 149-141 0 0 0 1 1.9 5.9 2 3.5 8.5 4 13.4 15.7 8 36.1 43.5012 60.7 72.1 18 85.0 86.9 Recovery 98.4 98.0

[0264] Other formulations of Oxybutynin wherein the pH modifying agentcomprises fumaric acid are set forth in Table 56 below: TABLE 56Component mg/tab (range) or % as noted 1. Sustained Release Excipient 170-234 mg 2. Fumaric Acid   15-60 mg 3. Oxybutynin HCL 5, 10, 15 mg 4.Silicon Dioxide 0-2% 5. Sodium Stearyl Fumarate 1-2%

[0265] The examples provided above are not meant to be exclusive. Manyother variations of the present invention would be obvious to thoseskilled in the art, and are contemplated to be within the scope of theappended claims.

What is claimed is:
 1. A sustained release oral solid dosage form comprising: an therapeutically effective amount of a medicament having a solubility of more than about 10 g/l; a pH modifying agent; a sustained release matrix comprising a gelling agent, said gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, said dosage form providing a sustained release of said medicament after oral administration to human patients.
 2. The sustained release oral solid dosage form of claim 1 which provides a sustained release of said medicament for at least about 12 hours after oral administration.
 3. The sustained release oral solid dosage form of claim 1 which provides a sustained release of said medicament for at least about 24 hours after oral administration.
 4. The sustained release oral solid dosage form of claim 1, wherein said medicament has a solubility of more than about 100 g/l.
 5. The sustained release oral solid dosage form of claim 1, wherein said medicament has a solubility of more than about 1000 g/l.
 6. The sustained release oral solid dosage form of claim 1, further comprising an inert pharmaceutical diluent.
 7. The sustained release oral solid dosage form of claim 6, wherein said inert diluent is selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof.
 8. The sustained release oral solid dosage form of claim 6, wherein the ratio of said inert diluent to said gelling agent is from about 1:3 to about 3:1
 9. The sustained release oral solid dosage form of claim 1, wherein the ratio of said medicament to said gelling agent is from about 1:5 to about 5:1.
 10. The sustained release oral solid dosage form of claim 1, further comprising an ionizable gel strength enhancing agent capable of crosslinking with said gelling agent and increasing the gel strength when the dosage form is exposed to an environmental fluid.
 11. The oral solid dosage form of claim 10, wherein said ionizable gel strength enhancing agent comprises an alkali metal or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate, or lactate.
 12. The oral solid dosage form of claim 11, wherein said ionizable gel strength enhancing comprises calcium sulfate.
 13. The oral solid dosage form of claim 1, wherein said heteropolysaccharide gum comprises xanthan gum and said homopolysaccharide gum comprises locust bean gum.
 14. The oral solid dosage form of claim 1, wherein said pH modifying agent is an organic acid.
 15. The sustained release oral solid dosage form of claim 14, wherein said organic acid is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and combinations thereof.
 16. The sustained release oral solid dosage form of claim 15, wherein said organic acid is fumaric acid.
 17. The oral solid dosage form of claim 1, wherein said pH modifying agent is present in an amount from about 1% to about 10%.
 18. The oral solid dosage form of claim 1, further comprising a surfactant.
 19. The oral solid dosage form of claim 18, wherein said surfactant is selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric (amphipathic/amphophilic) surfactants, and non-ionic surfactants.
 20. The oral solid dosage form of claim 18, wherein said surfactant is selected from the group consisting of sodium lauryl sulfate and a pharmaceutically effective salt of docusate.
 21. The oral solid dosage form of claim 1, wherein said sustained release matrix further comprises a hydrophobic material.
 22. The oral solid dosage form of claim 21, wherein said hydrophobic material is selected from the group consisting of an alkylcellulose, a copolymer of acrylic and methacrylic acid esters, waxes, shellac, zein, hydrogenated vegetable oil, and mixtures thereof, in an amount effective to slow the hydration of said gelling agent when exposed to an environmental fluid.
 23. The oral solid dosage form of claim 21, wherein said hydrophobic material is ethylcellulose.
 24. The oral solid dosage form of claim 5, wherein said sustained release matrix comprises from about 1 to about 20% by weight of said hydrophobic material.
 25. The oral solid dosage form of claim 1, further comprising from about 1 to about 10% by weight microcrystalline cellulose.
 26. The oral solid dosage form of claim 1, wherein said medicament is a benzothiazine.
 27. The oral solid dosage form of claim 26, wherein said benzothiazine is diltiazem or a pharmaceutically effective salt thereof.
 28. The oral solid dosage form of claim 27, which provides a sustained release of said diltiazem for at least about 12 hours after oral administration to human patients.
 29. The oral solid dosage form of claim 28 wherein said diltiazem is present in an amount from about 60 mg to about 120 mg.
 30. The oral solid dosage form of claim 27, which provides a sustained release of said diltiazem for at least about 24 hours after oral administration to human patients.
 31. The oral solid dosage form of claim 30 wherein said diltiazem is present in an amount from about 120 mg to about 300 mg.
 32. The oral solid dosage form of claim 1, wherein said medicament is an antispasmodic agent.
 33. The oral solid dosage form of claim 32, wherein said antispasmodic drug is oxybutynin or a pharmaceutically acceptable salt thereof.
 34. The oral solid dosage form of claim 33, wherein said antispasmodic agent is oxybutynin chloride.
 35. The oral solid dosage form of claim 33, which provides a sustained release of said oxybutynin for at least 12 hours after oral administration to human patients.
 36. The oral solid dosage form of claim 35, wherein said oxybutynin is present in an amount from about 2.5 mg to about 25 mg.
 37. The oral solid dosage form of claim 33, which provides a sustained release of said oxybutynin for at least about 24 hours after oral administration to human patients.
 38. The oral solid dosage form of claim 37, wherein said oxybutynin is present in an amount from about 5 mg to about 50 mg.
 39. The oral solid dosage form of claim 1 which is a tablet.
 40. The oral solid dosage form of claim 1 which is in granular form.
 41. The oral solid dosage form of claim 40, wherein a portion of said medicament is outside the granulation.
 42. The oral solid dosage form of claim 40, wherein a sufficient amount of said granules to provide an effective dose of said medicament are disposed in a pharmaceutically acceptable capsule.
 43. The oral solid dosage form of claim 39 wherein at least part of a surface of said tablet is coated with a hydrophobic material to a weight gain from about 1 to about 20 percent, by weight.
 44. The oral solid dosage form of claim 43, wherein said hydrophobic material is selected from the group consisting of an alkylcellulose, a copolymer of acrylic and methacrylic acid, waxes, shellac, zein, hydrogenated vegetable oils, and mixtures of any of the foregoing.
 45. The sustained release oral dosage form of claim 18 which provides bimodal absorption profile of said medicament.
 46. A sustained release oral solid dosage form comprising: an effective amount of a calcium channel blocker to provide a therapeutic effect, said calcium channel blocker having a solubility greater than 10 g/L; a pH modifying agent; a pharmaceutically acceptable surfactant a sustained release excipient comprising a gelling agent, said gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, said dosage form providing bimodal absorption profile of said calcium channel blocker and providing a sustained release of said calcium channel blocker for at least about 12 hours after oral administration to human patients.
 47. The oral solid dosage form of claim 46, wherein said calcium channel blocker is a benzothiazine.
 48. The oral solid dosage form of claim 46, wherein said benzothiazine is diltiazem or a pharmaceutically acceptable salt thereof.
 49. The oral solid dosage form of claim 48, wherein said dosage form provides an initial peak concentration (Cmax #1) of said diltiazem in about 4 to about 10 hours after oral administration of the dosage form, followed by a second peak concentration (Cmax #2) which occurs in about 10 to about 16 hours after oral administration of the dosage form, said dosage form providing a therapeutic effect for at least about 24 hours after oral administration to a human patient.
 50. The dosage form of claim 49, wherein said time to first peak plasma concentration (Tmax #1) of diltiazem occurs in about 6 to about 8 hours after oral administration of the dosage form to the patient.
 51. The dosage form of claim 49, wherein the maximum plasma concentration of diltiazem at the first. Tmax (Cmax #1) is from about 50 to about 100 ng/ml, per administration of a 240 mg dosage of diltiazem.
 52. The dosage form of claim 46, wherein the second peak plasma concentration (Cmax #2) occurs in about 12 to about 14 hours after oral administration of the dosage form to the patient (Tmax #2).
 53. The dosage form of claim 52, wherein the maximum plasma concentration of diltiazem at Cmax #2 is from about 60 to about 90 ng/ml, per 240 mg diltiazem.
 54. The dosage form of claim 46, wherein the width of the plasma concentration curve at 50% of the height of Cmax #1, based on a trough taken as the Cmin between Cmax #1 and. Cmax #2 is from about 0.5 to about 4.0 hours.
 55. The dosage form of claim 46, wherein the width of the plasma concentration curve at 50% of the height of Cmax #1, based on a trough taken as the Cmin between Cmax #1 and Cmax #2 is from about 1 to about 3 hours.
 56. The dosage form of claim 46, wherein the width of the plasma concentration curve at 50% of the height of Cmax #2, based on a the trough taken as the Cmin between Cmax #1 and Cmax #2 is from about 0.5 to about 8 hours.
 57. The dosage form of claim 46, wherein the width of the plasma concentration curve at 50% of the height of Cmax #2, based on a the trough taken as the Cmin between Cmax #1 and Cmax #2 is from about 2 to about 6 hours.
 58. The dosage form of claim 49, wherein the ratio of Cmax #1 to Cmax #2 is from about 0.5:1 to about 1.5:1.
 59. The dosage form of claim 58, wherein the ratio of Cmax #1 to Cmax #2 is from about 0.7:1 to about 1.2:1.
 60. A method of treating a human patient suffering from a disease state selected from the group consisting of hypertension, angina, aneurysms, arythmias, and headache comprising administering to said patient a dosage form of claim
 46. 61. A sustained release oral solid dosage form comprising: an effective amount of oxybutynin or a pharmaceutically acceptable salt thereof to provide a therapeutic effect, a pH modifying agent; a sustained release excipient comprising a gelling agent, said gelling agent comprises a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum, said dosage form providing a therapeutic effect for at least about 24 hours after administration to human patients.
 62. The sustained release oral solid dosage form of claim 61 which provides a time to peak plasma concentration (Tmax) in about 5 to about 15 hours
 63. The sustained release oral solid dosage form of claim 62 which provides a time to peak plasma concentration (Tmax) in about 8 to about 12 hours.
 64. A method of treating a human patient suffering from incontinence comprising administering to said patient a dosage form of claim
 61. 